Diamines as modulators of chemokine receptor activity

ABSTRACT

The present application describes modulators of MCP-1 of formula (I):  
                 
or pharmaceutically acceptable salt forms thereof, useful for the prevention of asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.

This application is a divisional of U.S. Ser. No. 10/027,505 filed Dec.20, 2001 now allowed, which claims priority from provisional applicationU.S. Ser. No. 60/256,855 filed Dec. 20, 2000, which is incorporatedherein by reference in its entirety.

FIELD OF THE INVENTION

This invention relates generally to modulators of chemokine receptoractivity, pharmaceutical compositions containing the same, and methodsof using the same as agents for treatment and prevention of inflammatorydiseases, allergic and autoimmune diseases, and in particular, asthma,rheumatoid arthritis, atherosclerosis, and multiple sclerosis.

BACKGROUND OF THE INVENTION

Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, thatare released by a wide variety of cells to attract and activate, amongother cell types, macrophages, T and B lymphocytes, eosinophils,basophils and neutrophils (reviewed in: Luster, New Eng. J. Med. 1998,338, 436-445 and Rollins, Blood 1997, 90, 909-928). There are two majorclasses of chemokines, CXC and CC, depending on whether the first twocysteines in the amino acid sequence are separated by a single aminoacid (CXC) or are adjacent (CC). The CXC chemokines, such asinterleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) andmelanoma growth stimulatory activity protein (MGSA) are chemotacticprimarily for neutrophils and T lymphocytes, whereas the CC chemokines,such as RANTES, MIP-1α, MIP-1β, the monocyte chemotactic proteins(MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (−1 and −2) arechemotactic for, among other cell types, macrophages, T lymphocytes,eosinophils, dendritic cells, and basophils. There also exist thechemokines lymphotactin-1, lymphotactin-2 (both C chemokines), andfractalkine (a CXXXC chemokine) that do not fall into either of themajor chemokine subfamilies.

The chemokines bind to specific cell-surface receptors belonging to thefamily of G-protein-coupled seven-transmembrane-domain proteins(reviewed in: Horuk, Trends Pharm. Sci. 1994, 15, 159-165) which aretermed “chemokine receptors.” On binding their cognate ligands,chemokine receptors transduce an intracellular signal though theassociated trimeric G proteins, resulting in, among other responses, arapid increase in intracellular calcium concentration, changes in cellshape, increased expression of cellular adhesion molecules,degranulation, and promotion of cell migration. There are at least tenhuman chemokine receptors that bind or respond to CC chemokines with thefollowing characteristic patterns: CCR-1 (or “CKR-1” or “CC-CKR-1”)[MIP-1α, MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell 1993, 72,415-425, and Luster, New Eng. J. Med. 1998, 338, 436-445); CCR-2A andCCR-2B (or “CKR-2A”/“CKR-2B” or “CC-CKR-2A”/“CC-CKR-2B”) [MCP-1, MCP-2,MCP-3, MCP-4, MCP-5] (Charo, et al., Proc. Natl. Acad. Sci. USA 1994,91, 2752-2756, and Luster, New Eng. J. Med. 1998, 338, 436-445); CCR-3(or “CKR-3” or “CC-CKR-3”) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4](Combadiere, et al., J. Biol. Chem. 1995, 270, 16491-16494, and Luster,New Eng. J. Med. 1998, 338, 436-445); CCR-4 (or “CKR-4” or “CC-CKR-4”)[TARC, MIP-1α, RANTES, MCP-1] (Power, et al., J. Biol. Chem. 1995, 270,19495-19500, and Luster, New Eng. J. Med. 1998, 338, 436-445); CCR-5 (or“CKR-5” OR “CC-CKR-5”) [MIP-1α, RANTES, MIP-1α] (Sanson, et al.,Biochemistry 1996, 35, 3362-3367); CCR-6 (or “CKR-6” or “CC-CKR-6”)[LARC] (Baba, et al., J. Biol. Chem. 1997, 272, 14893-14898); CCR-7 (or“CKR-7” or “CC-CKR-7”) [ELC] (Yoshie et al., J. Leukoc. Biol. 1997, 62,634-644); CCR-8 (or “CKR-8” or “CC-CKR-8”) [1-309, TARC, MIP-1β](Napolitano et al., J. Immunol., 1996, 157, 2759-2763, and Bernardini,et al., Eur. J. Immunol. 1998, 28, 582-588); CCR-10 (or “CKR-10” or“CC-CKR-10”) [MCP-1, MCP-3] (Bonini, et al., DNA and Cell Biol. 1997,16, 1249-1256); and CCR-11 [MCP-1, MCP-2, and MCP-4] (Schweickert, etal., J. Biol. Chem. 2000, 275, 90550).

In addition to the mammalian chemokine receptors, mammaliancytomegaloviruses, herpesviruses and poxviruses have been shown toexpress, in infected cells, proteins with the binding properties ofchemokine receptors (reviewed in: Wells and Schwartz, Curr. Opin.Biotech. 1997, 8, 741-748). Human CC chemokines, such as RANTES andMCP-3, can cause rapid mobilization of calcium via these virally encodedreceptors. Receptor expression may be permissive for infection byallowing for the subversion of normal immune system surveillance andresponse to infection. Additionally, human chemokine receptors, such asCXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co-receptors for theinfection of mammalian cells by microbes as with, for example, the humanimmunodeficiency viruses (HIV).

The chemokines and their cognate receptors have been implicated as beingimportant mediators of inflammatory, infectious, and immunoregulatorydisorders and diseases, including asthma and allergic diseases, as wellas autoimmune pathologies such as rheumatoid arthritis andatherosclerosis (reviewed in: Bharat K. Trivedi, et al, Ann. ReportsMed. Chem. 2000, 35, 191; John Saunders and Christine M. Tarby, DrugDisc. Today 1999, 4, 80; Brett A. Premack and Thomas J. Schall, NatureMedicine 1996, 2, 1174). For example, the chemokine monocytechemoattractant-1 (MCP-1) and its receptor CC Chekmokine Receptor 2(CCR-2) play a pivotal role in attracting leukocytes to sites ofinflammation and in subsequently activating these cells. When thechemokine MCP-1 binds to CCR-2, it induces a rapid increase inintracellular calcium concentration, increased expression of cellularadhesion molecules, cellular degranulation, and the promotion ofleukocyte migration. Demonstration of the importance of the MCP-1/CCR-2interaction has been provided by experiments with genetically modifiedmice. MCP-1−/− mice had normal numbers of leukocytes and macrophages,but were unable to recruit monocytes into sites of inflammation afterseveral different types of immune challenge (Bao Lu, et al., J. Exp.Med. 1998, 187, 601). Likewise, CCR-2−/− mice were unable to recruitmonocytes or produce interferon-γ when challenged with various exogenousagents; moreover, the leukocytes of CCR-2 null mice did not migrate inresponse to MCP-1 (Landin Boring, et al., J. Clin. Invest. 1997, 100,2552), thereby demonstrating the specificity of the MCP-1/CCR-2interaction. Two other groups have independently reported equivalentresults with different strains of CCR-2−/− mice (William A. Kuziel, etal., Proc. Natl. Acad. Sci. USA 1997, 94, 12053, and Takao Kurihara, etal., J. Exp. Med. 1997, 186, 1757). The viability and generally normalhealth of the MCP-1−/− and CCR-2−/− animals is noteworthy, in thatdisruption of the MCP-1/CCR-2 interaction does not induce physiologicalcrisis. Taken together, these data lead one to the conclusion thatmolecules that block the actions of MCP-1 would be useful in treating anumber of inflammatory and autoimmune disorders. This hypothesis has nowbeen validated in a number of different animal disease models, asdescribed below.

Several studies have demonstrated the potential therapeutic value ofantagonism of the MCP-1/CCR2 interaction in treating rheumatoidarthritis. A DNA vaccine encoding MCP-1 was shown recently to amelioratechronic polyadjuvant-induced arthritis in rats (Sawsan Youssef, et al.,J. Clin. Invest. 2000, 106, 361). Likewise, inflammatory diseasesymptoms could be controlled via direct administration of antibodies forMCP-1 to rats with collagen-induced arthritis (Hiroomi Ogata, et al., J.Pathol. 1997, 182, 106), or streptococcal cell wall-induced arthritis(Ralph C. Schimmer, et al., J. Immunol. 1998, 160, 1466). Perhaps mostsignificantly, a peptide antagonist of MCP-1, MCP-1 (9-76), was shownboth to prevent disease onset and to reduce disease symptoms (dependingon the time of administration) in the MRL-1pr mouse model of arthritis(Jiang-Hong Gong, et al., J. Exp. Med. 1997, 186, 131).

Three key studies have demonstrated the potential therapeutic value ofantagonism of the MCP-1/CCR2 interaction in treating atherosclerosis.For example, when MCP-1−/− mice are mated with LDL receptor-deficientmice, an 83% reduction in aortic lipid deposition was observed (Long Gu,et al., Mol. Cell 1998, 2, 275). Similarly, when MCP-1 was geneticallyablated from mice which already overexpressed human apolipoprotein B,the resulting mice were protected from atherosclerotic lesion formationrelative to the MCP-1+/+ apoB control mice (Jennifa Gosling, et al., J.Clin. Invest. 1999, 103, 773). Likewise, when CCR-2−/− mice are crossedwith apolipoprotein E mice, a significant decrease in the incidence ofatherosclerotic lesions was observed (Landin Boring, et al, Nature 1998,394, 894).

Other studies have demonstrated the potential therapeutic value ofantagonism of the MCP-1/CCR-2 interaction in treating multiplesclerosis; all of these studies have been demonstrated in experimentalautoimmune encephalomyelitis (EAE), the standard animal model formultiple scelerosis. Administration of antibodies for MCP-1 to animalswith EAE significantly diminished disease relapse (K. J. Kennedy, etal., J. Neuroimmunol. 1998, 92, 98). Furthermore, two recent reportshave now shown that CCR-2−/− mice are resistant to EAE (Brian T. Fife,et al., J. Exp. Med. 2000, 192, 899; Leonid Izikson, et al., J. Exp.Med. 2000, 192, 1075).

Other studies have demonstrated the potential therapeutic value ofantagonism of the MCP-1/CCR2 interaction in treating asthma.Sequestration of MCP-1 with a neutralizing antibody inovalbumin-challenged mice resulted in marked decrease in bronchialhyperresponsiveness and inflammation (Jose-Angel Gonzalo, et al., J.Exp. Med. 1998, 188, 157). It proved possible to reduce allergic airwayinflammation in Schistosoma mansoni egg-challenged mice through theadministration of antibodies for MCP-1 (Nicholas W. Lukacs, et al., J.Immunol. 1997, 158, 4398). Consistent with this, MCP-1−/− mice displayeda reduced response to challenge with Schistosoma mansoni egg (Bao Lu, etal., J. Exp. Med. 1998, 187, 601).

Other studies have demonstrated the potential therapeutic value ofantagonism of the MCP-1/CCR2 interaction in treating kidney disease.Administration of antibodies for MCP-1 in a murine model ofglomerularnephritis resulted in a marked decrease in glomerular crescentformation and deposition of type I collagen (Clare M. Lloyd, et al., J.Exp. Med. 1997, 185, 1371). In addition, MCP-1−/− mice with inducednephrotoxic serum nephritis showed significantly less tubular damagethan their MCP-1+/+counterparts (Gregory H. Tesch, et al., J. Clin.Invest. 1999, 103, 73).

One study has demonstrated the potential therapeutic value of antagonismof the MCP-1/CCR2 interaction in treating systemic lupus erythematosus.Crossing of MCP-1−/− mice with MRL-FAS^(1pr) mice—the latter of whichhave a fatal autoimmune disease that is analogous to human systemiclupus erythematosus—results mice that have less disease and longersurvival than the wildtype MRL-FAS^(1Pr) mice (Gregory H. Tesch, et al.,J. Exp. Med. 1999, 190, 1813).

One study has demonstrated the potential therapeutic value of antagonismof the MCP-1/CCR2 interaction in treating colitis. CCR-2−/− mice wereprotected from the effects of dextran sodium sulfate-induced colitis(Pietro G. Andres, et al., J. Immunol. 2000, 164, 6303).

One study has demonstrated the potential therapeutic value of antagonismof the MCP-1/CCR2 interaction in treating alveolitis. When rats with IgAimmune complex lung injury were treated intravenously with antibodiesraised against rat MCP-1 (JE), the symptoms of alveolitis were partiallyaleviated (Michael L. Jones, et al., J. Immunol. 1992, 149, 2147).

Other studies have provided evidence that MCP-1 is overexpressed invarious disease states not mentioned above. These reports provide strongcorrelative evidence that MCP-1 antagonists could be useful therapeuticsfor such diseases. Two reports described the overexpression of MCP-1 inthe intestinal epithelial cells and bowel mucosa of patients withinflammatory bowel disease (H. C. Reinecker, et al., Gastroenterology1995, 108, 40, and Michael C. Grimm, et al., J. Leukoc. Biol. 1996, 59,804). Two reports describe the overexpression of MCP-1 rats with inducedbrain trauma (J. S. King, et al., J. Neuroimmunol. 1994, 56, 127, andJoan W. Berman, et al., J. Immunol. 1996, 156, 3017). Another study hasdemonstrated the overexpression of MCP-1 in rodent cardiac allografts,suggesting a role for MCP-1 in the pathogenesis of transplantarteriosclerosis (Mary E. Russell, et al. Proc. Natl. Acad. Sci. USA1993, 90, 6086). The overexpression of MCP-1 has been noted in the lungendothelial cells of patients with idiopathic pulmonary fibrosis (HarryN. Antoniades, et al., Proc. Natl. Acad. Sci. USA 1992, 89, 5371).Similarly, the overexpression of MCP-1 has been noted in the skin frompatients with psoriasis (M. Deleuran, et al., J. Dermatol. Sci. 1996,13, 228, and R. Gillitzer, et al., J. Invest. Dermatol. 1993, 101, 127).Finally, a recent report has shown that MCP-1 is overexpressed in thebrains and cerebrospinal fluid of patients with HIV-1-associateddementia (Alfredo Garzino-Demo, WO 99/46991).

It should also be noted that CCR-2 has been implicated as a co-receptorfor some strains of HIV (B. J. Doranz, et al., Cell 1996, 85, 1149). Ithas also been determined that the use of CCR-2 as an HIV co-receptor canbe correlated with disease progression (Ruth I. Connor, et al., J. Exp.Med. 1997, 185, 621). This finding is consistent with the recent findingthat the presence of a CCR-2 mutant, CCR2-64I, is positively correlatedwith delayed onset of HIV in the human population (Michael W. Smith, etal., Science 1997, 277, 959). Although MCP-1 has not been implicated inthese processes, it may be that MCP-1 antagonists that act via bindingto CCR-2 may have beneficial therapeutic effects in delaying the diseaseprogression to AIDS in HIV-infected patients.

Recently, a number of groups have described the development of smallmolecule antagonists of MCP-1 (reviewed in: Bharat K. Trivedi, et al,Ann. Reports Med. Chem. 2000, 35, 191). Workers at Teijen and Combichemreported the use of cyclic amines (A) as MCP-1 (Tatsuki Shiota, et al.,WO 99/25686; Tatsuki Shiota, et al., WO 00/69815) and MIP-1α (ChristineTarby and Wilna Moree, WO 00/69820) antagonists. These compounds aredistinguished from those of the present invention (I) by the requirementfor the central cyclic amine grouping.

A number of other groups have also described the development of smallmolecule antagonists of the MCP-1/CCR-2 interaction. To date,indolopiperidines (Ian T. Forbes, et al., Bioorg. Med. Chem. Lett. 2000,10, 1803), spiropiperidines (Tara Mirzadegan, et al., J. Biol. Chem.2000, 275, 25562), quaternary amines (Masanori Baba, et al., Proc. Natl.Acad. Sci. 1999, 96, 5698), 2-substituted indoles (Alan Faull and JasonKettle, WO 00/46196; Andrew John Barker, et al., WO 99/07351; AndrewJohn Barker, et al., WO 99/07678), pyrazolone derivatives (JanakKhimchand Padia, et al., U.S. Pat. No. 6,011,052, 2000), 2-substitutedbenzimidazoles (David Thomas Connor, et al., WO 98/06703),N,N-dialkylhomopiperazines (T. Shiota, et al., WO 97/44329), bicyclicpyrroles (Andrew J. Barker, et al., WO 99/40913 and Andrew J. Barker, etal., WO 99/40914), and 5-aryl pentadienamides (K. G. Carson, et al.,Cambridge Health Tech Institute Chemokine Symposium, McLean, Va., USA,1999) have all been reported as MCP-1 antagonists. The foregoingreference compounds are readily distinguished structurally from thepresent invention by virtue of substantial differences in the terminalfunctionality, the attachment functionality, or the core functionality.The prior art does not disclose nor suggest the unique combination ofstructural fragments that embody in the novel compounds describedherein. Furthermore, the prior art does not disclose or suggest that thecompounds of the present invention would be antagonists of MCP-1.

It should be noted that CCR-2 is also the receptor for the chemokinesMCP-2, MCP-3, MCP-4, and MCP-5 (Luster, New Eng. J. Med. 1998, 338,436-445). Since it is presumed that the new compounds of formula (I)described herein antagonize MCP-1 by binding to the CCR-2 receptor, itmay be that these compounds of formula (I) are also effectiveantagonists of the actions of MCP-2, MCP-3, MCP-4, and MCP-5 that aremediated by CCR-2. Accordingly, when reference is made herein to“antagonism of MCP-1,” it is to be assumed that this is equivalent to“antagonism of chemokine stimulation of CCR-2.”

SUMMARY OF THE INVENTION

Accordingly, the present invention provides novel antagonists or partialagonists/antagonists of MCP-1 receptor activity, or pharmaceuticallyacceptable salts or prodrugs thereof.

The present invention provides pharmaceutical compositions comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of at least one of the compounds of the present invention or apharmaceutically acceptable salt or prodrug form thereof.

The present invention provides a method for treating rheumatoidarthritis, multiple sclerosis, and atherosclerosis, comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or a pharmaceutically acceptable salt or prodrug form thereof.

The present invention provides a method for treating inflammatorydiseases, comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

The present invention provides diamine compounds for use in therapy.

The present invention provides the use of novel diamine compounds forthe manufacture of a medicament for the treatment of inflammatorydiseases.

These and other features of the invention, which will become apparentduring the following detailed description, have been achieved by theinventors' discovery that compounds of formula (I):

-   -   or stereoisomers or pharmaceutically acceptable salts thereof,        wherein X, Z, l, m, n, s, R¹, R², R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹,        R¹², R¹⁴ and R^(14a) are defined below, are effective modulators        of chemokine activity.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] Thus, in a first embodiment, the present invention provides novelcompounds of formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein:

-   Z is selected from a bond, —C(O)—, —C(O)NH—, —C(S)NH—, —SO₂—, and    —SO₂NH—;-   X is selected from —NR¹⁷—, —O—, —S—, and —CHR¹⁶NR¹⁷—;-   R¹ is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁴ and a    5-10 membered heteroaryl system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R⁴;-   R² is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁵ and a    5-10 membered heteroaryl system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R⁵;-   R³ is selected from H, (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(3d),    (CRR)_(q)S(O)_(p)R^(3d), (CRR)_(r)C(O)R^(3b), (CRR)_(q)R^(3a)R^(3a),    (CRR)_(r)C(O)NR^(3a)R^(3a), (CRR)_(r)C(O)NR^(3a)OR^(3d),    (CRR)_(q)SO₂NR^(3a)R^(3a), (CRR)_(r)C(O)OR^(3d), a (CRR)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-5 R^(3e), and a    (CRR)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(3e);-   with the proviso that R³ is not H if R⁶ is H;-   alternatively, R³ and R¹² join to form a C₃₋₆ cycloalkyl substituted    with 0-2 R^(3g) a C₅₋₆ lactam substituted with 0-2 R^(3g), or a C₅₋₆    lactone substituted with 0-2 R^(3g);-   R^(3a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(3c), C₂₋₆ alkyl substituted with 0-3 R^(3e),    C₃₋₈ alkenyl substituted with 0-3 R^(3e), C₃₋₈ alkynyl substituted    with 0-3 R^(3e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-5 R^(3e), and a    (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(3e);-   R^(3b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0-3 R^(3e), C₂₋₈ alkenyl substituted with 0-3    R^(3e), C₂₋₈ alkynyl substituted with 0-3 R^(3e), a (CH₂)_(r)—C₃₋₆    carbocyclic residue substituted with 0-2 R^(3e), and a (CH₂)_(r)-5-6    membered heterocyclic system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R^(3e);-   R^(3c) is independently selected from —C(O)R^(3b), —C(O)OR^(3d),    —C(O)NR^(3f)R^(3f), and (CH₂)_(r)phenyl;-   R^(3d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0-3 R^(3e), C₃₋₆ alkenyl    substituted with 0-3 R^(3e), C₃₋₆ alkynyl substituted with 0-3    R^(3e), a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(3e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(3e);-   R^(3e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,    (CH₂)_(r)NR^(3f)R^(3f), and (CH₂)_(r)phenyl;-   R^(3f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆    cycloalkyl;-   R^(3g) is selected from (CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(3d),    (CHR)_(q)S(O)_(p)R^(3d), (CHR)_(r)C(O)R^(3b), (CHR)_(q)NR^(3a)R³    (CHR)_(r)C(O)NR^(3a)R^(3a), (CHR)_(r)C(O)NR^(3a)OR^(3d),    (CHR)_(q)SO₂NR^(3a)R^(3a), (CHR)_(r)C(O)OR^(3d), and a    (CHR)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(3e);-   R, at each occurrence, is independently selected from H, C₁₋₆ alkyl,    C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,    (CHR)_(r)C(O)NR^(3a)R^(3a), and (CHR)_(r)C(O)OR^(3d), and    (CH₂)_(r)phenyl substituted with R^(3e);-   R⁴, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(4a)R^(4a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CR′R′)_(r)R^(4d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,    (CR′R′)_(r)S(CR′R′)_(r)R^(4d), (CR′R′)_(r)C(O)OH,    (CR′R′)_(r)C(O)(CR′R′)_(r)R^(4b), (CR′R′)_(r)C(O)NR^(4a)R^(4a),    (CR′R′)_(r)NR^(4f)C(O)(CR′R′)_(r)R^(4b),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(4d),    (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(4b),    (CR′R′)_(r)NR^(4f)C(O)O(CR′R′)_(r)R^(4d),    (CR′R′)_(r)OC(O)NR^(4a)R^(4a),    (CR′R′)_(r)NR^(6a)C(S)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(4a)C(O)NR^(4a)R^(4a), (CR′R′)_(r)C(═NR^(4f))    NR^(4a)R^(4a), (CR′R′)_(r)NHC(═NR^(4f))NR^(4f)R^(4f),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(4b), (CR′R′)_(r)S(O)₂NR^(4a)R^(4a),    (CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a),    (CR′R′)_(r)NR^(4f)S(O)₂(CR′R′)_(r)R^(4b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, and (CR′R′)_(r)phenyl substituted with 0-3 R^(4e);-   alternatively, two R⁴ on adjacent atoms on R¹ may join to form a    cyclic acetal;-   R^(4a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(4g), C₂₋₆ alkyl substituted with 0-2 R^(5e),    C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted    with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-5 R^(4e), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(4e);-   R^(4b), at each occurrence, is selected from C₁₋₆ alkyl substituted    with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈    alkynyl substituted with 0-2 R^(5e), a (CH₂)_(r)C₃₋₆ carbocyclic    residue substituted with 0-3 R^(4e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 6-2 R^(4e);-   R^(4d), at each occurrence, is selected from C₃₋₈ alkenyl    substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with 0-2    R^(5e), methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(4e), a    (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(4e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(4e);-   R^(4e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(4f)R^(4f), and (CH₂)_(r)phenyl;-   R^(4f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆    cycloalkyl, and phenyl;-   R^(4g) is independently selected from —C(O)R^(4b), —C(O)OR^(4d),    —C(O)NR^(4f)R^(4f), and (CH₂)_(r)phenyl;-   R⁵, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(5a)R^(5a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CR′R′)_(r)R^(5d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,    (CR′R′)_(r)S(CR′R′)_(r)R^(5d), (CR′R′)_(r)C(O)OH,    (CR′R′)_(r)C(O)(CR′R′)_(r)R^(5b), (CR′R′)_(r)C(O)NR^(5a)R^(5a),    (CR′R′)_(r)NR^(5f)C(O)(CR′R′)_(r)R^(5b),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(5d),    (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(5b),    (CR′R′)_(r)NR^(5f)C(O)O(CR′R′)_(r)R^(5d),    (CR′R′)_(r)OC(O)NR^(5a)R^(5a), (CR′R′)_(r)NR^(5a)C(O)NR^(5a)R^(5a),    (CR′R′)_(r)C(═NR^(5f))NR^(5a)R^(5a),    (CR′R′)_(r)NHC(═NR^(5f))NR^(5f)R^(5f),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(5b), (CR′R′)_(r)S(O)₂NR^(5a)R^(5a),    (CR′R′)_(r)NR^(5a)S(O)₂NR^(5a)R^(5a),    (CR′R′)_(r)NR^(5f)S(O)₂(CR′R′)_(r)R^(5b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, and (CR′R′)_(r)phenyl substituted with 0-3 R^(5e);-   alternatively, two R⁵ on adjacent atoms on R² may join to form a    cyclic acetal;-   R^(5a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(5g), C₂₋₆ alkyl substituted with 0-2 R^(5e),    C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted    with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-5 R^(5e), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(5e);-   R^(5b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2    R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), a (CH₂)_(r)C₃₋₆    carbocyclic residue substituted with 0-3 R^(5e), and a (CH₂)_(r)-5-6    membered heterocyclic system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-2 R^(5e);-   R^(5d), at each occurrence, is independently selected from C₃₋₈    alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with    0-2 R^(5e), methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(5e), a    (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(5e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(5e);-   R^(5e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(5f)R^(5f), and (CH₂)_(r)phenyl;-   R^(5f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆    cycloalkyl, and phenyl;-   R^(5g) is independently selected from —C(O)R^(5b), —C(O)OR^(5d),    —C(O)NR^(5f)R^(5f), and (CH₂)_(r)phenyl;-   R′, at each occurrence, is selected from H, C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl    substituted with R^(5e);-   R⁶, is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(6d), (CRR)_(q)S(O)_(p)R^(6d),    (CRR)_(r)C(O)R^(6b), (CRR)_(r)NR^(6a)R^(6a),    (CRR)_(r)C(O)NR^(6a)R^(6a), (CRR)_(r)C(O)NR^(6a)OR^(6d),    (CRR)SO₂NR^(6a)R^(6a), (CRR)_(r)C(O)OR^(6d), a (CRR)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-5 R^(6e), and a    (CRR)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(6e);-   alternatively, R⁶ and R⁷ join to form a C₃₋₆ cycloalkyl substituted    with 0-2 R^(6g) a 5-6 membered ring lactam substituted with 0-2    R^(6g), or a 5-6 membered ring lactone substituted with 0-2 R^(6g);-   R^(6a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl substituted with 0-3 R^(6e), C₃₋₈ alkenyl    substituted with 0-3 R^(6e), C₃₋₈ alkynyl substituted with 0-3    R^(6e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(6e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(6e);-   R^(6b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0-3 R^(6e), C₂₋₈ alkenyl substituted with 0-3    R^(6e), C₂₋₈ alkynyl substituted with 0-3 R^(6e), a (CH₂)_(r)—C₃₋₆    carbocyclic residue substituted with 0-2 R^(6e), and a (CH₂)_(r)-5-6    membered heterocyclic system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R^(6e);-   R^(6d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0-3 R^(6e), C₃₋₆ alkenyl    substituted with 0-3 R^(6e), C₃₋₆ alkynyl substituted with 0-3    R^(6e), a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(6e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(6e);-   R^(6e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;-   R^(6f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R^(6g) is selected from (CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(6d),    (CHR)_(q)S(O)_(p)R^(6d), (CHR)_(r)C(O)R^(6b),    (CHR)_(q)NR^(6a)R^(6a), (CHR)_(r)C(O)NR^(6a)R^(6a),    (CHR)_(r)C(O)NR^(6a)OR^(6d), (CHR)_(q)SO₂NR^(6a)R^(6a),    (CHR)_(r)C(O)OR^(6d), and a (CHR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-5 R^(6e);-   R⁷, is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(7d), (CRR)_(q)S(O)_(p)R^(7d),    (CRR)_(r)C(O)R^(7b), (CRR)_(r)NR^(7a)R^(7a),    (CRR)_(r)C(O)NR^(7a)R^(7a), (CRR)_(r)C(O)NR^(7a)OR^(7d),    (CRR)_(q)SO₂NR^(7a)R^(7a), (CRR)_(r)C(O)OR^(7d), a (CRR)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-5 R^(7e), and a    (CRR)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(7e);-   R^(7a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl substituted with 0-3 R^(7e), C₃₋₈ alkenyl    substituted with 0-3 R^(7e), C₃₋₈ alkynyl substituted with 0-3    R^(7e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(7e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(7e);-   R^(7b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0-3 R^(7e), C₂₋₈ alkenyl substituted with 0-3    R^(7e), C₂₋₈ alkynyl substituted with 0-3 R^(7e), a (CH₂)_(r)—C₃₋₆    carbocyclic residue substituted with 0-2 R^(7e), and a (CH₂)_(r)-5-6    membered heterocyclic system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R^(7e);-   R^(7d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0-3 R^(7e), C₃₋₆ alkenyl    substituted with 0-3 R^(7e), C₃₋₆ alkynyl substituted with 0-3    R^(7e), a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(7e);-   R^(7e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;-   R^(7f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R⁸ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(8d), (CRR)_(r)S(O)_(p)R^(8d),    (CRR)_(r)C(O)R^(8b), (CRR)_(r)NR^(8a)R^(8a),    (CRR)_(r)C(O)NR^(8a)R^(8a), (CRR)_(r)C(O)NR^(8a)OR^(8d),    (CRR)_(r)SO₂NR^(8a)R^(8a), (CRR)_(r)C(O)OR^(8d), a (CRR)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-5 R^(8e), and a    (CRR)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(8e);-   alternatively, R⁸ and R⁹ join to form a C₃₋₆ cycloalkyl substituted    with 0-2 R^(8g) a 5-6 memebered ring lactam substituted with 0-2    R^(8g), or a 5-6 membered ring lactone substituted with 0-2 R^(8g);-   R^(8a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl substituted with 0-3 R^(8e), C₃₋₈ alkenyl    substituted with 0-3 R^(8e), C₃₋₈ alkynyl substituted with 0-3    R^(8e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(8e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(8e);-   R^(8b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0-3 R^(8e), C₂₋₈ alkenyl substituted with 0-3    R^(8e), C₂₋₈ alkynyl substituted with 0-3 R^(8e), a (CH₂)_(r)—C₃₋₆    carbocyclic residue substituted with 0-2 R^(8e), and a (CH₂)_(r)-5-6    membered heterocyclic system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R^(8e);-   R^(8d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0-3 R^(8e), C₃₋₆ alkenyl    substituted with 0-3 R^(8e), C₃₋₆ alkynyl substituted with 0-3    R^(8e), a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(8e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(8e);-   R^(8e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₁₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(8f)R^(8f), and (CH₂)_(r)phenyl;-   R^(8f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R^(8g) is selected from (CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(8d),    (CHR)_(q)S(O)_(p)R^(8d), (CHR)_(r)C(O)R^(8b),    (CHR)_(q)NR^(8a)R^(8a), (CHR)_(r)C(O)NR^(8a)R^(8a),    (CHR)_(r)C(O)NR^(8a)OR^(8d), (CHR)_(q)SO₂NR^(8a)R^(8a),    (CHR)_(r)C(O)OR^(8d), and a (CHR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-5 R^(8e);-   R⁹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(9d), (CRR)_(r)S(O)_(p)R^(9d),    (CRR)_(r)C(O)R^(9b), (CRR)_(r)NR^(9a)R^(9a),    (CRR)_(r)C(O)NR^(9a)R^(9a), (CRR)_(r)C(O)NR^(9a)OR^(9d),    (CRR)_(r)SO₂NR^(9a)R^(9a), (CRR)_(r)C(O)OR^(9d), a (CRR)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-5 R^(9e), and a    (CRR)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(9e);-   R^(9a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl substituted with 0-3 R^(9e), C₃₋₈ alkenyl    substituted with 0-3 R^(9e), C₃₋₈ alkynyl substituted with 0-3    R^(9e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(9e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(9e);-   R^(9b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0-3 R^(9e), C₂₋₈ alkenyl substituted with 0-3    R^(9e), C₂₋₈ alkynyl substituted with 0-3 R^(9e), a (CH₂)_(r)—C₃₋₆    carbocyclic residue substituted with 0-2 R^(9e), and a (CH₂)_(r)-5-6    membered heterocyclic system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R^(9e);-   R^(9d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0-3 R^(9e), C₃₋₆ alkenyl    substituted with 0-3 R^(9e), C₃₋₆ alkynyl substituted with 0-3    R^(9e), a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(9e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(9e);-   R^(9e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₁₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(9f)R^(9f), and (CH₂)_(r)phenyl;-   R^(9f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R¹⁰ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(10d),    (CRR)_(r)S(O)_(p)R^(10d), (CRR)_(r)C(O)R^(10b),    (CRR)_(r)NR^(10a)R^(10a), (CRR)_(r)C(O)NR^(10a)R^(10a),    (CRR)_(r)C(O)NR^(10a)OR^(10d), (CRR)_(r)SO₂NR^(10a)R^(10a),    (CRR)_(r)C(O)OR^(10d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-5 R^(10e), and a (CRR)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(10e); alternatively, R¹⁰ and R¹¹ join    to form a C₃₋₆ cycloalkyl substituted with 0-2 R^(10g) a 5-6    membered ring lactam substituted with 0-2 R^(10g), or a 5-6 membered    ring lactone substituted with 0-2 R^(10g);-   R^(10a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl substituted with 0-3 R^(10e), C₃₋₈ alkenyl    substituted with 0-3 R^(10e), C₃₋₈ alkynyl substituted with 0-3    R^(10e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(10e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(10e);-   R^(10b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0-3 R^(10e), C₂₋₈ alkenyl substituted with    0-3 R^(10e), C₂₋₈ alkynyl substituted with 0-3 R^(10e), a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(10e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(10e);-   R^(10d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0-3 R^(10e), C₃₋₆ alkenyl    substituted with 0-3 R^(10e), C₃₋₆ alkynyl substituted with 0-3    R^(10e), a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(10e),    and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(10e);-   R^(10e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(10f)R^(10f), and (CH₂)_(r)phenyl;-   R^(10f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R^(10g) is selected from (CHR)_(q)OH, (CHR)_(q)SH,    (CHR)_(q)OR^(10d), (CHR)_(q)S(O)_(p)R^(10d), (CHR)_(r)C(O)R^(10b),    (CHR)_(q)NR^(10a)R^(10a), (CHR)_(r)C(O)NR^(10a)R^(10a),    (CHR)_(r)C(O)NR^(10a)O (CHR)_(q)SO₂NR^(10a)R^(10a),    (CHR)_(r)C(O)OR^(10d), and a (CHR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-5 R^(10e);-   R¹¹, is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(11d),    (CRR)_(r)S(O)_(p)R^(11d), (CRR)_(r)C(O)R^(11b),    (CRR)_(r)NR^(11a)R^(11a), (CRR)_(r)C(O)NR^(11a)R^(11a),    (CRR)_(r)C(O)NR^(11a)OR^(11d), (CRR)_(r)SO₂NR^(11a)R^(11a),    (CRR)_(r)C(O)OR^(11d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-5 R^(11e), and a (CRR)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(11e);-   R^(11a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl substituted with 0-3 R^(11e), C₃₋₈ alkenyl    substituted with 0-3 R^(11e), C₃₋₈ alkynyl substituted with 0-3    R^(11e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(11e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(11e);-   R^(11b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0-3 R^(11e), C₂₋₈ alkenyl substituted with    0-3 R^(11e), C₂₋₈ alkynyl substituted with 0-3 R^(11e), a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(11e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e);-   R^(11d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0-3 R^(11e), C₃₋₆ alkenyl    substituted with 0-3 R^(11e), C₃₋₆ alkynyl substituted with 0-3    R^(11e), a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(11e),    and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e);-   R^(11e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl;-   R^(11f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R¹² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(12d),    (CRR)_(q)S(O)_(p)R^(12d), (CRR)_(r)C(O)R^(12b),    (CRR)_(r)NR^(12a)R^(12a), (CRR)_(r)C(O)NR^(12a)R^(12a),    (CRR)_(r)C(O)NR^(12a)OR^(12d), (CRR)_(q)SO₂NR^(12a)R^(12a),    (CRR)_(r)C(O)OR^(12d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-5 R^(12e), and a (CRR)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(12e);-   R^(12a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl substituted with 0-3 R^(12e), C₃₋₈ alkenyl    substituted with 0-3 R^(12e), C₃₋₈ alkynyl substituted with 0-3    R^(12e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(12e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(12e);-   R^(12b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0-3 R^(12e), C₂₋₈ alkenyl substituted with    0-3 R^(12e), C₂₋₈ alkynyl substituted with 0-3 R^(12e), a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(12e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e);-   R^(12d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0-3 R^(12e), C₃₋₆ alkenyl    substituted with 0-3 R^(12e), C₃₋₆ alkynyl substituted with 0-3    R^(12e), a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(12e),    and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e);-   R^(12e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₁₆ alkyl, SH,    (CH₂)_(r)SC₁₋₁₅ alkyl, (CH₂)_(r)NR^(12f)R^(12f), and    (CH₂)_(r)phenyl;-   R^(12f), at each occurrence, is selected from H, C₁₋₆ alkyl, and    C₃₋₆ cycloalkyl;-   R¹⁴ and R^(14a) are independently selected from H, and C₁₋₄alkyl    substituted with 0-1 R^(14b), alternatively, R¹⁴ and R^(14a) can    join to form a C₃₋₆ cycloalkyl;-   R^(14b), at each occurrence, is independently selected from —OH,    —SH, —NR^(14c)R^(14c), —C(O)NR^(14c)R^(14c), —NHC(O)R^(14c) and    phenyl;-   R^(14c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   R¹⁵ is selected from H, C₁₋₄ alkyl, and C₃₋₆ cycloalkyl;-   R¹⁶ is selected from H, C₁₋₄ alkyl substituted with 0-3 R^(16a), and    C₃₋₆ cycloalkyl substituted with 0-3 R^(16a);-   R^(16a) is selected from C₁₋₄ alkyl, —OH, —SH, —NR^(16c)R^(16c),    —C(O)NR^(16c)R^(16c), and —NHC(O)R^(16c);-   R^(16c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   R¹⁷ is selected from H, C₁₋₄ alkyl, and C₃₋₄ cycloalkyl;-   n is selected from 1 and 2;-   l is selected from 0 and 1;-   m is selected from 0 and 1;-   p, at each occurrence, is selected from 0, 1, or 2;-   q, at each occurrence, is selected from 1, 2, 3, or 4; and-   r, at each occurrence, is selected from 0, 1, 2, 3, or 4.

[2] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   Z is selected from a bond, —C(O)—, —C(O)NH—, —C(S)NH—, —SO₂—, and    —SO₂NH—;-   X is selected from —NR¹⁷—, —O—, —S—, and —CHR¹⁶NR¹⁷—;-   R¹ is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁴ and a    5-10 membered heteroaryl system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R⁴;-   R² is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁵ and a    5-10 membered heteroaryl system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R⁵;-   R³ is selected from (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(3d),    (CRR)_(q)S(O)_(p)R^(3d), (CRR)_(r)C(O)R^(3b),    (CRR)_(g)NR^(3a)R^(3a), (CRR)_(r)C(O)NR^(3a)R^(3a),    (CRR)_(r)C(O)NR^(3a)OR^(3d), (CRR)_(q)SO₂NR^(3a)R^(3a),    (CRR)_(r)C(O)OR^(3d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-5 R^(3e), and a (CRR)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(3e);-   alternatively, R³ and R¹² join to form a C₃₋₆ cycloalkyl substituted    with 0-2 R^(3g) a C₅₋₆ lactam substituted with 0-2 R^(3g), or a C₅₋₆    lactone substituted with 0-2 R^(3g);-   R^(3a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(3c), C₂₋₆ alkyl substituted with 0-3 R^(3e),    C₃₋₈ alkenyl substituted with 0-3 R^(3e), C₃₋₈ alkynyl substituted    with 0-3 R^(3e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-5 R^(3e), and a    (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(3e);-   R^(3b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0-3 R^(3e), C₂₋₈ alkenyl substituted with 0-3    R^(3e), C₂₋₈ alkynyl substituted with 0-3 R^(3e), a (CH₂)_(r)—C₃₋₆    carbocyclic residue substituted with 0-2 R^(3e), and a (CH₂)_(r)-5-6    membered heterocyclic system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R^(3e);-   R^(3c) is independently selected from —C(O)R^(3b), —C(O)OR^(3d),    —C(O)NR^(3f)R^(3f), and (CH₂)_(r)phenyl;-   R^(3d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0-3 R^(3e), C₃₋₆ alkenyl    substituted with 0-3 R^(3e), C₃₋₆ alkynyl substituted with 0-3    R^(3e), a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(3e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(3e);-   R^(3e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,    (CH₂)_(r)NR^(3f)R^(3f), and (CH₂)_(r)phenyl;-   R^(3f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆    cycloalkyl;-   R^(3g) is selected from (CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(3d),    (CHR)_(q)S(O)_(p)R^(3d), (CHR)_(r)C(O)R^(3b), (CHR)_(q)R^(3a)R^(3a),    (CHR)_(r)C(O)NR^(3a)R^(3a), (CHR)_(r)C(O)NR^(3a)OR^(3d),    (CHR)_(q)SO₂NR^(3a)R^(3a), (CHR)_(r)C(O)OR^(3d), and a    (CHR)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(3e);-   R, at each occurrence, is independently selected from H, C₁₋₆ alkyl,    C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,    (CHR)_(r)C(O)NR^(3a)R^(3a), and (CHR)_(r)C(O)OR^(3d), and    (CH₂)_(r)phenyl substituted with R^(3e);-   R⁴, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(4a)R^(4a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CR′R′)_(r)R^(4d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,    (CR′R′)_(r)S(CR′R′)_(r)R^(4d), (CR′R′)_(r)C(O)OH,    (CR′R′)_(r)C(O)(CR′R′)_(r)R^(4b), (CR′R′)_(r)C(O)NR^(4a)R^(4a),    (CR′R′)_(r)NR^(4f)C(O)(CR′R′)_(r)R^(4b),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(4d),    (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(4b),    (CR′R′)_(r)NR^(4f)C(O)O(CR′R′)_(r)R^(4d),    (CR′R′)_(r)OC(O)NR^(4a)R^(4a),    (CR′R′)_(r)NR^(6a)C(S)NR^(6a)(CR′R′)_(r)R^(6d),    (CR′R′)_(r)NR^(4a)C(O)NR^(4a)R^(4a),    (CR′R′)_(r)C(═NR^(4f))NR^(4a)R^(4a),    (CR′R′)_(r)NHC(═NR^(4f))NR^(4f)R^(4f),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(4b), (CR′R′)_(r)S(O)₂NR^(4a)R^(4a),    (CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a),    (CR′R′)_(r)NR^(4f)S(O)₂(CR′R′)_(r)R^(4b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3    R′, and (CR′R′)_(r)phenyl substituted with 0-3 R^(4e);-   alternatively, two R⁴ on adjacent atoms on R¹ may join to form a    cyclic acetal;-   R^(4a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(4g), C₂₋₆ alkyl substituted with 0-2 R^(5e),    C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted    with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-5 R^(4e), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(4e);-   R^(4b), at each occurrence, is selected from C₁₋₆ alkyl substituted    with 0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈    alkynyl substituted with 0-2 R^(5e), a (CH₂)_(r)C₃₋₆ carbocyclic    residue substituted with 0-3 R^(4e), and a (CH₂)_(r)-5-6 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-2 R^(4e);-   R^(4d), at each occurrence, is selected from C₃₋₈ alkenyl    substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with 0-2    R^(5e), methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(4e), a    (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(4e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(4e);-   R^(4e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(4f)R^(4f), and (CH₂)_(r)phenyl;-   R^(4f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆    cycloalkyl, and phenyl;-   R^(4g) is independently selected from —C(O)R^(4b), —C(O)OR^(4d),    —C(O)NR^(4f)R^(4f), and (CH₂)_(r)phenyl;-   R⁵, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(5a)R^(5a), (CR′R′)_(r)OH,    (CR′R′)_(r)O(CR′R′)_(r)R^(5d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,    (CR′R′)_(r)S(CR′R′)_(r)R^(5d), (CR′R′)_(r)C(O)OH,    (CR′R′)_(r)C(O)(CR′R′)_(r)R^(5b), (CR′R′)_(r)C(O)NR^(5a)R^(5a),    (CR′R′)_(r)NR^(5f)C(O)(CR′R′)_(r)R^(5b),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(5d),    (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(5b),    (CR′R′)_(r)NR^(5f)C(O)O(CR′R′)_(r)R^(5d),    (CR′R′)_(r)OC(O)NR^(5a)R^(5a), (CR′R′)_(r)NR^(5a)C(O)NR^(5a)R^(5a),    (CR′R′)_(r)C(═NR^(5f))NR^(5a)R^(5a),    (CR′R′)_(r)NHC(═NR^(5f))NR^(5f)R^(5f),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(5b), (CR′R′)_(r)S(O)₂NR^(5a)R^(5a),    (CR′R′)_(r)NR^(5a)S(O)₂NR^(5a)R^(5a),    (CR′R′)_(r)NR^(5f)S(O)₂(CR′R′)_(r)R^(5b), C₁₋₆ haloalkyl, C₂₋₈    alkenyl substituted with 0-3 R₁, C₂₋₈ alkynyl substituted with 0-3    R′, and (CR′R′)_(r)phenyl substituted with 0-3 R^(5e);-   alternatively, two R⁵ on adjacent atoms on R² may join to form a    cyclic acetal;-   R^(5a), at each occurrence, is independently selected from H, methyl    substituted with 0-1 R^(5g), C₂₋₆ alkyl substituted with 0-2 R^(5e),    C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted    with 0-2 R^(5e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0-5 R^(5e), and a (CH₂)_(r)-5-10 membered heterocyclic system    containing 1-4 heteroatoms selected from N, O, and S, substituted    with 0-2 R^(5e); R^(5b), at each occurrence, is independently    selected from C₁₋₆ alkyl substituted with 0-2 R^(5e), C₃₋₈ alkenyl    substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with 0-2    R^(5e), a (CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3    R^(5e), and a (CH₂)_(r)—S-6 membered heterocyclic system containing    1-4 heteroatoms selected from N, O, and S, substituted with 0-2    R^(5e);-   R^(5d), at each occurrence, is independently selected from C₃₋₈    alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with    0-2 R^(5e), methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(5e), a    (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(5e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(5e);-   R^(5e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r) NR^(5f)R^(5f), and (CH₂)_(r)phenyl;-   R^(5f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆    cycloalkyl, and phenyl;-   R^(5g) is independently selected from —C(O)R^(5b), —C(O)OR^(5d),    —C(O)NR^(5f)R^(5f), and (CH₂)_(r)phenyl;-   R′, at each occurrence, is selected from H, C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl    substituted with R^(5e);-   R⁶, is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(6d), (CRR)_(q)S(O)_(p)R^(6d),    (CRR)_(r)C(O)R^(6b), (CRR)_(r)NR^(6a)R^(6a),    (CRR)_(r)C(O)NR^(6a)R^(6a), (CRR)_(r)C(O)NR^(6a)OR^(6d),    (CRR)SO₂NR^(6a)R^(6a), (CRR)_(r)C(O)OR^(6d), a (CRR)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-5 R^(6e), and a    (CRR)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(6e);    alternatively, R⁶ and R⁷ join to form a C₃₋₆ cycloalkyl substituted    with 0-2 R^(6g) a 5-6 membered ring lactam substituted with 0-2    R^(6g), or a 5-6 membered ring lactone substituted with 0-2 R^(6g);-   R^(6a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl substituted with 0-3 R^(6e), C₃₋₈ alkenyl    substituted with 0-3 R^(6e), C₃₋₈ alkynyl substituted with 0-3    R^(6e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(6e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(6e);-   R^(6b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0-3 R^(6e), C₂₋₈ alkenyl substituted with 0-3    R^(6e), C₂₋₈ alkynyl substituted with 0-3 R^(6e), a (CH₂)_(r)—C₃₋₆    carbocyclic residue substituted with 0-2 R^(6e), and a (CH₂)_(r)-5-6    membered heterocyclic system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R^(6e);-   R^(6d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0-3 R^(6e), C₃₋₆ alkenyl    substituted with 0-3 R^(6e), C₃₋₆ alkynyl substituted with 0-3    R^(6e), a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(6e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(6e);-   R^(6e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;-   R^(6f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R^(6g) is selected from (CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(6d),    (CHR)_(q)S(O)_(p)R^(6d), (CHR)_(r)C(O)R^(6b),    (CHR)_(q)NR^(6a)R^(6a), (CHR)_(r)C(O)NR^(6a)R^(6a),    (CHR)_(r)C(O)NR^(6a)OR^(6d), (CHR)_(q)SO₂NR^(6a)R^(6a),    (CHR)_(r)C(O)OR^(6d), and a (CHR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-5 R^(6e);-   R⁷, is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(7d), (CRR)_(q)S(O)_(p)R^(7d),    (CRR)_(r)C(O)R^(7b), (CRR)_(r)NR^(7a)R^(7a),    (CRR)_(r)C(O)NR^(7a)R^(7a), (CRR)_(r)C(O)NR^(7a)OR^(7d),    (CRR)_(q)SO₂NR^(7a)R^(7a), (CRR)_(r)C(O)OR^(7d), a (CRR)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-5 R^(7e), and a    (CRR)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(7e);-   R^(7a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl substituted with 0-3 R^(7e), C₃₋₈ alkenyl    substituted with 0-3 R^(7e), C₃₋₈ alkynyl substituted with 0-3    R^(7e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(7e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(7e);-   R^(7b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0-3 R^(7e), C₂₋₈ alkenyl substituted with 0-3    R^(7e), C₂₋₈ alkynyl substituted with 0-3 R^(7e), a (CH₂)_(r)—C₃₋₆    carbocyclic residue substituted with 0-2 R^(7e), and a (CH₂)_(r)-5-6    membered heterocyclic system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R^(7e);-   R^(7d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0-3 R^(7e), C₃₋₆ alkenyl    substituted with 0-3 R^(7e), C₃₋₆ alkynyl substituted with 0-3    R^(7e), a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(7e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(7e);-   R^(7e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₁₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;-   R^(7f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R⁸ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(8d), (CRR)_(r)S(O)_(p)R^(8d),    (CRR)_(r)C(O)R^(8b), (CRR)_(r)NR^(8a)R^(8a),    (CRR)_(r)C(O)NR^(8a)R^(8a), (CRR)_(r)C(O)NR^(8a)OR^(8d),    (CRR)_(r)SO₂NR^(8a)R^(8a), (CRR)_(r)C(O)OR^(8d), a (CRR)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-5 R^(8e), and a    (CRR)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(8e);-   alternatively, R⁸ and R⁹ join to form a C₃₋₆ cycloalkyl substituted    with 0-2 R^(8g) a 5-6 memebered ring lactam substituted with 0-2    R^(8g), or a 5-6 membered ring lactone substituted with 0-2 R^(8g);-   R^(8a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl substituted with 0-3 R^(8e), C₃₋₈ alkenyl    substituted with 0-3 R^(8e), C₃₋₈ alkynyl substituted with 0-3    R^(8e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(8e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(8e);-   R^(8b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0-3 R^(8e), C₂₋₈ alkenyl substituted with 0-3    R^(8e), C₂₋₈ alkynyl substituted with 0-3 R^(8e), a (CH₂)_(r)—C₃₋₆    carbocyclic residue substituted with 0-2 R^(8e), and a (CH₂)_(r)-5-6    membered heterocyclic system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R^(8e);-   R^(8d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0-3 R^(8e), C₃₋₆ alkenyl    substituted with 0-3 R^(8e), C₃₋₆ alkynyl substituted with 0-3    R^(8e), a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(8e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(8e);-   R^(8e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(8f)R^(8f), and (CH₂)_(r)phenyl;-   R^(8f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R^(8g) is selected from (CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(8d),    (CHR)_(q)S(O)_(p)R^(8d), (CHR)_(r)C(O)R^(8b),    (CHR)_(q)NR^(8a)R^(8a), (CHR)_(r)C(O)NR^(8a)R^(8a),    (CHR)_(r)C(O)NR^(8a)OR^(8d), (CHR)_(q)SO₂NR^(8a)R^(8a),    (CHR)_(r)C(O)OR^(8d), and a (CHR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-5 R^(8e);-   R⁹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(9d), (CRR)_(r)S(O)_(p)R^(9d),    (CRR)_(r)C(O)R^(9b), (CRR)_(r)NR^(9a)R^(9a),    (CRR)_(r)C(O)NR^(9a)R^(9a), (CRR)_(r)C(O)NR^(9a)OR^(9d),    (CRR)_(r)SO₂NR^(9a)R^(9a), (CRR)_(r)C(O)OR^(9d), a (CRR)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-5 R^(9e), and a    (CRR)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(9e);-   R^(9a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl substituted with 0-3 R^(9e), C₃₋₈ alkenyl    substituted with 0-3 R^(9e), C₃₋₈ alkynyl substituted with 0-3    R^(9e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(9e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(9e);-   R^(9b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0-3 R^(9e), C₂₋₈ alkenyl substituted with 0-3    R^(9e), C₂₋₈ alkynyl substituted with 0-3 R^(9e), a (CH₂)_(r)—C₃₋₆    carbocyclic residue substituted with 0-2 R^(9e), and a (CH₂)_(r)-5-6    membered heterocyclic system containing 1-4 heteroatoms selected    from N, O, and S, substituted with 0-3 R^(9e);-   R^(9d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0-3 R^(9e), C₃₋₆ alkenyl    substituted with 0-3 R^(9e), C₃₋₆ alkynyl substituted with 0-3    R^(9e), a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(9e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(9e);-   R^(9e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(9f)R^(9f), and (CH₂)_(r)phenyl;-   R^(9f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R¹⁰ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(10d),    (CRR)_(r)S(O)_(p)R^(10d), (CRR)_(r)C(O)R^(10b),    (CRR)_(r)NR^(10a)R^(10a), (CRR)_(r)C(O)NR^(10a)R^(10a),    (CRR)_(r)C(O)NR^(10a)OR^(10d), (CRR)_(r)SO₂NR^(10a)R^(10a),    (CRR)_(r)C(O)OR^(10d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-5 R^(10e), and a (CRR)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(10e);-   alternatively, R¹⁰ and R¹¹ join to form a C₃₋₆ cycloalkyl    substituted with 0-2 R^(10g) a 5-6 membered ring lactam substituted    with 0-2 R^(10g), or a 5-6 membered ring lactone substituted with    0-2 R^(10g);-   R^(10a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl substituted with 0-3 R^(10e), C₃₋₈ alkenyl    substituted with 0-3 R^(10e), C₃₋₈ alkynyl substituted with 0-3    R^(10e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(10e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(10e);-   R^(10b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0-3 R^(10e), C₂₋₈ alkenyl substituted with    0-3 R^(10e), C₂₋₈ alkynyl substituted with 0-3 R^(10e), a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(10e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(10e);-   R^(10d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0-3 R^(10e), C₃₋₆ alkenyl    substituted with 0-3 R^(10e), C₃₋₆ alkynyl substituted with 0-3    R^(10e), a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(10e),    and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(10e);-   R^(10e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(10f)R^(10f), and (CH₂)_(r)phenyl;-   R^(10f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R^(10g) is selected from (CHR)_(q)OH, (CHR)_(q)SH,    (CHR)_(q)OR^(10d), (CHR)_(q)S(O)_(p)R^(10d), (CHR)_(r)C(O)R^(10b),    (CHR)_(q)NR^(10a)R^(10a), (CHR)_(r)C(O)NR^(10a)R^(10a),    (CHR)_(r)C(O)NR^(10a)OR^(10d), (CHR)_(q)SO₂NR^(10a)R^(10a),    (CHR)_(r)C(O)OR^(10d), and a (CHR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-5 R^(10e);-   R¹¹, is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(11d),    (CRR)_(r)S(O)_(p)R^(11d), (CRR)_(r)C(O)R^(11b),    (CRR)_(r)NR^(11a)R^(11a), (CRR)_(r)C(O)NR^(11a)R^(11a),    (CRR)_(r)C(O)NR^(11a)OR^(11d), (CRR)_(r)SO₂NR^(11a)R^(11a),    (CRR)_(r)C(O)OR^(11d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-5 R^(11e), and a (CRR)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(11e);-   R^(11a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl substituted with 0-3 R^(11e), C₃₋₈ alkenyl    substituted with 0-3 R^(11e), C₃₋₈ alkynyl substituted with 0-3    R^(11e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(11e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(11e);-   R^(11b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0-3 R^(11e), C₂₋₈ alkenyl substituted with    0-3 R^(11e), C₂₋₈ alkynyl substituted with 0-3 R^(11e), a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(11e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e);-   R^(11d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0-3 R^(11e), C₃₋₆ alkenyl    substituted with 0-3 R^(11e), C₃₋₆ alkynyl substituted with 0-3    R^(11e), a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(11e),    and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(11e);-   R^(11e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₁₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl;-   R^(11f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R¹² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(12d),    (CRR)_(q)S(O)_(p)R^(12d), (CRR)_(r)C(O)R¹²b,    (CRR)_(r)NR^(12a)R^(12a), (CRR)_(r)C(O)NR^(12a)R^(12a),    (CRR)_(r)C(O)NR^(12a)OR^(12d), (CRR)_(q)SO₂NR^(12a)R^(12a),    (CRR)_(r)C(O)OR^(12d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-5 R^(12e), and a (CRR)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(12e);-   R^(12a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl substituted with 0-3 R^(12e), C₃₋₈ alkenyl    substituted with 0-3 R^(12e), C₃₋₈ alkynyl substituted with 0-3    R^(12e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-5 R^(12e), and a (CH₂)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(12e);-   R^(12b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0-3 R^(12e), C₂₋₈ alkenyl substituted with    0-3 R^(12e), C₂₋₈ alkynyl substituted with 0-3 R^(12e), a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(12e), and    a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e);-   R^(12d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0-3 R^(12e), C₃₋₆ alkenyl    substituted with 0-3 R^(12e), C₃₋₆ alkynyl substituted with 0-3    R^(12e), a C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(12e),    and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(12e);-   R^(12e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(12f)R^(12f), and (CH₂)_(r)phenyl;-   R^(12f), at each occurrence, is selected from H, C₁₋₆ alkyl, and    C₃₋₆ cycloalkyl;-   R¹⁴ and R^(14a) are independently selected from H, and C₁₋₄alkyl    substituted with 0-1 R^(14b),-   alternatively, R¹⁴ and R^(14a) can join to form a C₃₋₆ cycloalkyl;-   R^(14b), at each occurrence, is independently selected from —OH,    —SH, —NR^(14c)R^(14c), —C(O)NR^(14c)R^(14c), —NHC(O)R^(14c) and    phenyl;-   R^(14c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   R¹⁵ is selected from H, C₁₋₄ alkyl, and C₃₋₆ cycloalkyl;-   R¹⁶ is selected from H, C₁₋₄ alkyl substituted with 0-3 R^(16a), and    C₃₋₆ cycloalkyl substituted with 0-3 R^(16a);-   R^(16a) is selected from C₁₋₄ alkyl, —OH, —SH, —NR^(16c)R^(16c),    —C(O)NR^(16c)R^(16c), and —NHC(O)R^(16c); R^(16c) is selected from    H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   R¹⁷ is selected from H, C₁₋₄ alkyl, and C₃₋₄ cycloalkyl;-   n is selected from 1 and 2;-   l is selected from 0 and 1;-   m is selected from 0 and 1;-   p, at each occurrence, is selected from 0, 1, or 2;-   q, at each occurrence, is selected from 1, 2, 3, or 4; and-   r, at each occurrence, is selected from 0, 1, 2, 3, or 4.

[3] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   R¹⁴ and R^(14a) are H;-   R¹⁵ is H; and-   n is 1.

[4] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   R¹⁶ is selected from H, C₁₋₄ alkyl substituted with 0-1 R^(16a),    wherein the alkyl is selected from methyl, ethyl, propyl, i-propyl,    butyl, i-butyl, and s-butyl, and C₃₋₄ cycloalkyl substituted with    0-3 R^(16a) wherein the cycloalkyl is selected from cyclopropyl and    cyclobutyl;-   R^(16a) is selected from methyl, ethyl, propyl, i-propyl, —OH, —SH,    —NR^(16c)R^(16c), —C(O)NR^(16c)R^(16c), and —NHC(O)R^(16c); and-   R¹⁷ is selected from H, methyl, ethyl, propyl, and i-propyl.

[5] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   R⁹ and R¹¹ are H; and-   R⁸ and R¹⁰ are independently selected from H, C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue wherein    the carbocyclic residue is selected from cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl, phenyl and naphthyl.

[6] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   R³ is selected from (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(3d),    (CRR)_(q)S(O)_(p)R^(3d), (CRR)_(r)C(O)R^(3b),    (CRR)_(q)NR^(3a)R^(3a), (CRR)_(r)C(O)NR^(3a)R^(3a),    (CRR)_(r)C(O)NR^(3a)OR^(3d), (CRR)_(q)SO₂NR^(3a)R^(3a),    (CRR)_(r)C(O)OR^(3d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0-5 R^(3e), and a (CRR)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-3 R^(3e) wherein the heterocyclic system    is selected from pyridinyl, thiophenyl, furanyl, indazolyl,    benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl,    benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl,    indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl,    piperidinyl, pyrrazolyl, pyrrolidinyl, tetrahydrofuranyl,    tetrahydrothiophenyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl,    thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl;-   R⁶ is selected from H, (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(6d),    (CRR)_(q)S(O)_(p)R^(6d), (CRR)_(r)C(O)R^(6b),    (CRR)_(q)NR^(6a)R^(6a), (CRR)_(r)C(O)NR^(6a)R^(6a),    (CRR)_(r)C(O)NR^(6a)OR^(6d), (CRR)_(q)SO₂NR^(6a)R^(6a),    (CRR)_(r)C(O)OR^(6d), a (CRR)_(r)—C₆₋₁₀ carbocyclic residue    substituted with 0-5 R^(6e), and a (CRR)_(r)-5-10 membered    heterocyclic system containing 1-4 heteroatoms selected from N, O,    and S, substituted with 0-6 R^(6e) wherein the heterocyclic system    is selected from pyridinyl, thiophenyl, furanyl, indazolyl,    benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl,    benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl,    indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl,    piperidinyl, pyrrazolyl, pyrrolidinyl, tetrahydrofuranyl,    tetrahydrothiophenyl, 1,2,4-triazolyl, 1,2,6-triazolyl, tetrazolyl,    thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl;-   R⁷ is H;-   R¹² is selected from H, methyl, ethyl, and propyl;-   alternatively, R³ and R¹² join to form a C₃₋₆ cycloalkyl substituted    with 0-2 R^(3g) a C₅₋₆ lactam substituted with 0-2 R^(3g), or a C₅₋₆    lactone substituted with 0-2 R^(3g).

[7] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   R¹ is selected from phenyl substituted with 0-3 R⁴ and a 5-10    membered heteroaryl system substituted with 0-3 R⁴, wherein the    heteroaryl is selected from benzimidazolyl, benzofuranyl,    benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl,    benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,    cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl    isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl,    pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl,    quinolinyl, thiazolyl, thienyl, and tetrazolyl;-   R² is selected from phenyl substituted with 0-3 R⁵ and a 5-10    membered heteroaryl system containing 1-4 heteroatoms substituted    with 0-3 R⁵, wherein the heteroaryl system is selected from    benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl,    benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,    benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl, imidazolyl,    indazolyl, indolyl, isoquinolinyl isothiazolyl, isoxazolyl,    oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl,    pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and    tetrazolyl.

[8] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   X is CHR¹⁶R¹⁷;-   R⁴, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CR′R′)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(4a)R^(4a), (CR′R′)_(r)OH, (CR′R′)_(r)OR^(4d),    (CR′R′)_(r)SH, (CR′R′)_(r)SR^(4d), (CR′R′)_(r)C(O)OH,    (CR′R′)_(r)C(O)R^(4b), (CR′R′)_(r)C(O)NR^(4a)R^(4a),    (CR′R′)_(r)NR^(4f)C(O)R^(4b), (CR′R′)_(r)C(O)OR^(4d),    (CR′R′)_(r)OC(O)R^(4b), (CR′R′)_(r)NR^(4f)C(O)OR^(4d),    (CR′R′)_(r)OC(O)NR^(4a)R^(4a), (CR′R′)_(r)NR^(4a)C (O)NR^(4a)R^(4a),    (CR′R′)_(r)S(O)_(p)R^(4b), (CR′R′)_(r)S(O)₂NR^(4a)R^(4a),    (CR′R′)_(r)NR^(4f)S(O)₂R^(4b), (CR′R′)_(r)NR^(4f)S(O)₂    NR^(4a)R^(4a), C₁₋₆ haloalkyl, and (CR′R′)_(r)phenyl substituted    with 0-3 R^(4e);-   alternatively, two R⁴ on adjacent atoms join to form —O—(CH₂)—O—;-   R^(4a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl,    pentyl, hexyl, allyl, propargyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic    residue selected from cyclopropyl, cyclobutyl, cyclopentyl and    cyclohexyl;-   R^(4b), at each occurrence, is selected from methyl, ethyl, propyl,    i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl, allyl,    propargyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3    R^(4e), wherein the carbocyclic residue is selected from    cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and a    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(4e),    wherein the heterocyclic system is selected from pyridinyl,    thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,    benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl,    quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl,    isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl,    1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl,    thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl;-   R^(4d), at each occurrence, is selected from H, methyl, CF₃, ethyl,    propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl,    allyl, propargyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue selected    from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;-   R^(4e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(4f)R^(4f), and (CH₂)_(r)phenyl;-   R^(4f), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, and cyclopropyl, cyclobutyl, and phenyl;-   R⁵, at each occurrence, is selected from methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, hexyl,    (CR′R′)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(5a)R^(5a), (CR′R′)_(r)OH, (CR′R′)_(r)OR^(5d),    (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)SR^(5d),    (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)R^(5b),    (CR′R′)_(r)C(O)NR^(5a)R^(5a), (CR′R′)_(r)NR^(5f)C(O)R^(5b),    (CR′R′)_(r)C(O)OR^(5d), (CR′R′)_(r)OC(O)R^(5b),    (CR′R′)_(r)NR^(5f)C(O)OR^(5d), (CR′R′)_(r)OC(O)NR^(5a)R^(5a),    (CR′R′)_(r)NR^(5a)C(O)NR^(5a)R^(5a),    (CR′R′)_(r)NR^(7a)C(O)NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7a)C(O)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)S(O)_(p)R^(5b),    (CR′R′)_(r)S(O)₂NR^(5a)R^(5a), (CR′R′′)_(r)NR^(5f)S(O)₂R^(5b), C₁₋₆    haloalkyl, and (CHR′)_(r)phenyl substituted with 0-3 R^(5e);-   alternatively, two R⁵ on adjacent atoms join to form —O— (CH₂)—O—;-   R^(5a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl,    pentyl, hexyl, allyl, propargyl, and a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0-1 R^(5e), wherein the carbocyclic residue    is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    phenyl and naphthyl;-   R^(5b), at each occurrence, is selected from methyl, ethyl, propyl,    i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl, allyl,    propargyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue selected from    cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl; and a    (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, wherein the heterocyclic    system is selected from pyridinyl, thiophenyl, furanyl, indazolyl,    azetidinyl, benzothiazolyl, benzimidazolyl, benzothiophenyl,    benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,    isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl,    isothiadiazolyl, isoxazolyl, morphlinyl, piperidinyl, pyrrolyl,    2,5-dihydropyrrolyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl,    tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and    pyrimidinyl;-   R^(5d), at each occurrence, is selected from H, methyl, CF₃, ethyl,    propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl,    allyl, propargyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue selected    from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;-   R^(5e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₁₅    alkyl, (CH₂)_(r)NR^(4f)R^(4f), and (CH₂)_(r)phenyl; and-   R^(5f), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, and cyclopropyl, cyclobutyl, and phenyl.

[9] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   R⁵ is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,    s-butyl, pentyl, hexyl, CF₃, CF₂CF₃, CF₂H, OCF₃, Cl, Br, I, F, SCF₃,    NR^(5a)R^(5a), NHC(O)OR^(5a), NHC(O)R^(5b), and NHC(O)NHR^(5a); and-   R¹² is selected from H and methyl.

[10] In another embodiment, the present invention provides compounds offormula (I), wherein

-   Z is —C(O)—;-   X is —CHR¹⁶NR¹⁷—;-   R¹ is selected from phenyl substituted with 0-3 R⁴, and a 5-10    membered heteroaryl system substituted with 0-2 R⁴, wherein the    heteroaryl is selected from indolyl, and pyridyl;-   R² is phenyl substituted with 0-2 R⁵;-   R³ is selected from (CRR)_(q)OH, (CRR)_(q)OR^(3d), (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)NR^(3a)R^(3a), (CHR)_(r)C(O)NR^(3a)OR^(3d),    (CH₂)C(O)R^(3b), (CH₂)_(r)C(O)OR^(3d), and (CH₂)-phenyl;-   alternatively, R³ and R¹² join to form cyclopropyl, cyclopentyl or    cyclohexyl;-   R^(3a) is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, s-butyl, t-butyl, allyl, CH₂CF₃, C(CH₃)CH₂CH₂OH,    cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl,    cyclohexyl, phenyl, and benzyl;-   R^(3b) is selected from pyrrolidinyl, pyrrolid-3-enyl, and    morpholinyl;-   R^(3d) is selected from methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl and benzyl;-   R is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, s-butyl, pentyl, neopentyl, phenyl and benzyl;-   R⁴ is selected from methyl, ethyl, propyl, i-propyl, butyl,    ethylene, OCH₃, OCF₃, SCH₃, SO₂CH₃, Cl, F, Br, CN;-   alternatively, two R⁴ join to form —O—(CH₂)—O—;-   R⁶ is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    C(O)OCH₃, C(O)NHCH₂CH₃;-   R⁷, R⁹, and R¹¹ are H;-   R⁸ is H;-   R¹⁰ is selected from H and methyl;-   R¹⁶ is selected from H and methyl;-   R¹⁷ is selected from H and methyl;-   m is 0 or 1;-   l is 0 or 1-   r is 0 or 1; and-   q is 1.

[11] In another embodiment, the present invention provides compounds offormula (I), wherein

-   R³ is H; and-   R⁶, is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(6d), (CRR)_(q)S(O)_(p)R^(6d),    (CRR)_(r)C(O)R^(6b), (CRR)_(r)NR^(6a)R^(6a),    (CRR)_(r)C(O)NR^(6a)R^(6a), (CRR)_(r)C(O)NR^(6a)OR^(6d),    (CRR)SO₂NR^(6a)R^(6a), (CRR)_(r)C(O)OR^(6d), a (CRR)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0-5 R^(6e), and a    (CRR)_(r)-5-10 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-3 R^(6e).

[12] In another embodiment, the present invention provides compounds offormula (I), wherein

-   R¹⁴ and R^(14a) are H;-   R¹⁵ is H;-   n is 1;-   R¹⁶ is selected from H, C₁₋₄ alkyl substituted with 0-1 R^(16a),    wherein the alkyl is selected from methyl, ethyl, propyl, i-propyl,    butyl, i-butyl, and s-butyl, and C₃₋₄ cycloalkyl substituted with    0-3 R¹⁶a wherein the cycloalkyl is selected from cyclopropyl and    cyclobutyl;-   R^(16a) is selected from methyl, ethyl, propyl, i-propyl, —OH, —SH,    —NR^(16c)R^(16c), —C(O)NR^(16c)R^(16c), and —NHC(O)R^(16c);-   R¹⁷ is selected from H, methyl, ethyl, propyl, and i-propyl;-   R⁹ and R¹¹ are H; and-   R⁸ and R¹⁰ are independently selected from H, C₁₋₆ alkyl, C₂₋₆    alkenyl, C₂₋₆ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue wherein    the carbocyclic residue is selected from cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl, phenyl and naphthyl.

[13] In another embodiment, the present invention provides compounds offormula (I), wherein

-   X is CHR¹⁶R¹⁷;-   R⁵ is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,    s-butyl, pentyl, hexyl, CF₃, CF₂CF₃, CF₂H, OCF₃, Cl, Br, I, F, SCF₃,    NR^(5a)R^(5a), NHC(O)OR^(5a), NHC(O)R^(5b), and NHC(O)NHR^(5a); and-   R¹² is selected from H and methyl;-   Z is —C(O)—;-   R¹ is selected from phenyl substituted with 0-3 R⁴, and a 5-10    membered heteroaryl system substituted with 0-2 R⁴, wherein the    heteroaryl is selected from indolyl, and pyridyl;-   R² is phenyl substituted with 0-2 R⁵;-   R³ is selected from (CRR)_(q)OH, (CRR)_(q)OR^(3d), (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)NR^(3a)R^(3a), (CHR)_(r)C(O)NR^(3a)OR^(3d),    (CH₂)C(O)R^(3b), (CH₂)_(r)C(O)OR^(3d), and (CH₂)-phenyl;-   alternatively, R³ and R¹² join to form cyclopropyl, cyclopentyl or    cyclohexyl;-   R^(3a) is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, s-butyl, t-butyl, allyl, CH₂CF₃, C(CH₃)CH₂CH₂OH,    cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl,    cyclohexyl, phenyl, and benzyl;-   R^(3b) is selected from pyrrolidinyl, pyrrolid-3-enyl, and    morpholinyl;-   R^(3d) is selected from methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl and benzyl;-   R is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, s-butyl, pentyl, neopentyl, phenyl and benzyl;-   R⁴ is selected from methyl, ethyl, propyl, i-propyl, butyl,    ethylene, OCH₃, OCF₃, SCH₃, SO₂CH₃, Cl, F, Br, CN;-   alternatively, two R⁴ join to form —O—(CH₂)—O—;-   R⁶ is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    C(O)OCH₃, C(O)NHCH₂CH₃;-   R⁷, R⁹, and R¹¹ are H;-   R⁸ is H;-   R¹⁰ is selected from H and methyl;-   R¹⁶ is selected from H and methyl;-   R¹⁷ is selected from H and methyl;-   m is 0 or 1;-   l is 0 or 1-   r is 0 or 1; and-   q is 1.

[14] In another embodiment, the present invention provides novelcompounds of formula (I), wherein the compound is selected from:

-   Methyl    (2S)-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate;-   Methyl    (2R)-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate;-   (2S)-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoic    acid;-   (2S)-N-Methyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2R)-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-Ethyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-Benzyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-Isopropyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-Cyclopropyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-Cyclobutyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-Phenyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N,N-Dimethyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-Methyl,N-methoxy-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   Methyl    (2S)-3-[[(4-chlorophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate;-   (2S)-3-[[(4-chlorophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-Ethyl-3-[[(4-chlorophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   Methyl    (2S)-3-[[(1S/R)-1-(4-chlorophenyl)ethyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate;-   Methyl    (2S)-3-[[(1S/R)-1-(2,4-dimethylphenyl)ethyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate;-   Methyl    (2S)-3-[(1H-indol-3-ylmethyl)amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate;-   (2S)-3-[(1H-indol-3-ylmethyl)amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   Methyl    (2S)-3-[(1,3-benzodioxol-5-ylmethyl)amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate;-   Methyl    (2S)-3-[[(4-bromophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate;-   Methyl    (2S)-2-[[[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanoate;-   Methyl    (2S)-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanoate;-   (2S)-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   N-[2-[[(1S)-2-[[(2,4-dimethylphenyl)methyl]amino]-1-(hydroxymethyl)ethyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1R)-2-[[(2,4-dimethylphenyl)methyl]amino]-1-(hydroxymethyl)ethyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S/R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxypropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   tert-Butyl    (3R)-4-[[(2,4-dimethylphenyl)methyl]amino]-3-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanoate;-   N-[2-[[(1R)-2-[[(2,4-dimethylphenyl)methyl]amino]-1-(phenylmethyl)ethyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   (2S)-N-tert-Butyl-2-[[[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(4-bromo,    2-methylphenyl)methyl]amino]-2-[[[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(4-bromo,    2-methylphenyl)methyl]amino]-propanamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-3-(methyl)butyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-3-(methyl)butyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(phenyl)ethyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(phenyl)ethyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-3-(phenyl)propyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-3-(phenyl)propyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-4-(methyl)pentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-4(methyl)pentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)butyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)butyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)butyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)butyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-4-(methyl)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-4-(methyl)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-4-(methyl)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-4-(methyl)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-4,4-dimethyl-2-(hydroxy)pentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-4,4-dimethyl-2-(hydroxy)pentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-3-amino-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-3-amino-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(ethylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(ethylamino)    carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(isopropylamino)    carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(isopropylamino)    carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[(1-pyrrolidinylcarbonyl)amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[(1-azetidinylcarbonyl)amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(methylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(4-mopholinylcarbonyl)]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(1-piperazinylcarbonyl)]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(4-ethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(4-ethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(4-ethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(isopropylamino)    carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(4-ethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[(4-morpholinylcarbonyl)amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(4-dimethylamino-2-methylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(4-dimethylamino-2-methylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-(tert-butyl)amino-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-isopropylamino-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-benzylamino-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(methoxy)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(methoxy)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;-   N-[2-[[(S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(methyl)propyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(methyl)propyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;-   N-[2-[[(S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(ethyl)butyl]amino]-2-oxoethyl]-2[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(ethyl)butyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;-   N-[2-[[(S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(propyl)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(propyl)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;-   N-[2-[[(S)-2-[[(2,4-dimethylphenyl)methyl]amino]-1-(hydroxycyclopentyl)ethyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(S)-1-[[(S)-2-[[(2,4-dimethylphenyl)methyl]amino]-1-(hydroxycyclopentyl)ethyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;-   (2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethoxy)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(difluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3(trifluoromethylthio)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(pentafluoroethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[[2-amino-5-(trifluoromethoxy)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[[2-amino-5-(methyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-ethylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-propylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-isobutylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[[2-butylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[[2-cyclohexylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-isopropylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-(tert-butyl)amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-(methylaminocarbonyl)amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-(isopropoxycarbonyl)amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-(isopropylaminocarbonyl)amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[[2-(cyclohexylcarbonyl)amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[[2-benzylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[[2-(para-chloro)benzylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[[2-[(beta-napthyl)methyl]amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[[2-(meta-methyl)benzylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[[2-(para-methyl)benzylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[[2-(ortho-methyl)benzylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-(para-trifluoromethyl)benzylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[β-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[[3-benzylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[[3-methylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[[3-ethylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[[3-isobutylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[[3-propylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[[3-butylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[[3-(trifluoromethylcarbonyl)amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-2-[[[[3-(ethoxycarbonyl)amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;-   (2S)-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2-methyl-4-bromophenyl)methyl]amino]-propanamide;-   (2S)-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(4-bromophenyl)methyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(4-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(4-bromophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(4-bromo-2-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   10    (2S)-N-tert-Butyl-3-[[(4-methoxyphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(4-methoxy-2-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(2-methoxypyridin-5-yl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(2,3-dimethyl-4-methoxy-phenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(4-cyano-2-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(4-ethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(2-methyl-4-vinylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(4-ethyl-2-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(4-isopropylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(4-butylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(4-dimethylaminophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(4-dimethylamino-2-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(4-methylthiophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(4-methylsulfonylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(4-trifluoromethoxyphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(3-amino-4-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(indol-3-yl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(2-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-3-[[(2-ethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2R)-N-Ethyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2R)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2R)-N-[(2-methyl)hydroxyprop-2-yl]-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Amyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-[(2-methyl)hydroxyprop-2-yl]-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-[(1-methyl)cycloprop-1-yl]-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-Cyclopentyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-Cyclohexyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-(β,β,β-Trifluoro)ethyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-Allyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-Cyclopropylmethyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   N-[2-[[(2S)-3-[[(2,4-dimethylphenyl)methyl]amino]-1-(pyrrolid-3-enyl)-1-oxopropyl-2-amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(2S)-3-[[(2,4-dimethylphenyl)methyl]amino]-1-(pyrrolidinyl)-1-oxopropyl-2-amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(2S)-3-[[(2,4-dimethylphenyl)methyl]amino]-1-(morpholinyl)-1-oxopropyl-2-amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   (2S)-N-Isobutyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-sec-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   (2S)-N-tert-Butyl-4-[[(2,4-dimethylphenyl)methyl]amino]-3-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide;-   (2S,3R)-N-Ethyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide;-   (2S,3R)-N-Ethyl-3-[[(4-bromophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide;-   Methyl    (2R)-2-[[(2,4-dimethylphenyl)methyl]amino]-3-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate;-   (2R)-N-Ethyl-2-[[(2,4-dimethylphenyl)methyl]amino]-3-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   Methyl    (2S)-4-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanoate;-   (2S)-4-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide;-   (2S)-N-Ethyl-4-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide;-   (2S)-N-Ethyl-4-[[(2,4-dimethylphenyl)methyl]methylamino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide;-   (2S)-N-tert-Butyl-2-[[[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-4-[[(2,4-dimethylphenyl)methyl]amino]-butanamide;-   (2S)-N-tert-Butyl-2-[[[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-4-[[(2,4-dimethylphenyl)methyl]methylamino]-butanamide;-   (2S)-N-tert-Butyl-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-4-[[(2,4-dimethylphenyl)methyl]amino]-butanamide;-   (2S)-N-tert-Butyl-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-4-[[(2,4-dimethylphenyl)methyl]methylamino]-butanamide;-   (2S)-N-tert-Butyl-2-[[[[3-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-4-[[(2,4-dimethylphenyl)methyl]amino]-butanamide;-   (2S)-N-tert-Butyl-2-[[[[3-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-4-[[(4-ethylphenyl)methyl]amino]-butanamide;-   (2S)-N-tert-Butyl-4-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide;-   (2S)-N-tert-Butyl-4-[[(4-ethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide;-   (2S)-N-Ethyl-5-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-pentanamide;-   N-[2-[[(1S,2S/R)-1-[[[(2,4-dimethylphenyl)methyl]methylamino]methyl]-2-hydroxy-3-(methyl)butyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]methylamino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(isopropylamino)    carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]isopropylamino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(isopropylamino)    carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(4-ethylphenyl)methyl]methylamino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(isopropylamino)    carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[(1S,2S)-1-[[[(4-ethylphenyl)methyl]isopropylamino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(isopropylamino)    carbonyl]amino]-5-(trifluoromethyl)benzamide;-   (2S)-N-t    ert-Butyl-3-[[(2,4-dimethylphenyl)methyl]methylamino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;-   N-[2-[[1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[1-[[[(4-chlorophenyl)methyl]amino]methyl]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;-   N-[2-[[1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]cyclopentyl]amino    ]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]cyclopropyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;-   N-[2-[[1-[(2,4-dimethylphenyl)methyl]amino]methyl]cyclopropyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;    and-   (2S)-N-Ethyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-2-methyl-propanamide.

In another embodiment, the present invention is directed to apharmaceutical composition, comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method formodulation of chemokine or chemokine receptor activity comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of Formula (I).

In another embodiment, the present invention is directed to a method formodulation of MCP-1, MCP-2, MCP-3 and MCP-4, and MCP-5 activity that ismediated by the CCR2 receptor comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method formodulation of MCP-1 activity comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method fortreating or preventing disorders, comprising administering to a patientin need thereof a therapeutically effective amount of a compound ofFormula (I), said disorders being selected from osteoarthritis,aneurism, fever, cardiovascular effects, Crohn's disease, congestiveheart failure, autoimmune diseases, HIV-infection, HIV-associateddementia, psoriasis, idiopathic pulmonary fibrosis, transplantarteriosclerosis, physically- or chemically-induced brain trauma,inflammatory bowel disease, alveolitis, colitis, systemic lupuserythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma,multiple sclerosis, artherosclerosis, and rheumatoid arthritis.

In another embodiment, the present invention is directed to a method fortreating or preventing disorders, of Formula (I), wherein said disordersbeing selected from psoriasis, idiopathic pulmonary fibrosis, transplantarteriosclerosis, physically- or chemically-induced brain trauma,inflammatory bowel disease, alveolitis, colitis, systemic lupuserythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma,multiple sclerosis, artherosclerosis, and rheumatoid arthritis.

In another embodiment, the present invention is directed to a method fortreating or preventing disorders, of Formula (I), wherein said disordersbeing selected from alveolitis, colitis, systemic lupus erythematosus,nephrotoxic serum nephritis, glomerularnephritis, asthma, multiplesclerosis, artherosclerosis, and rheumatoid arthritis.

In another embodiment, the present invention is directed to a method fortreating or preventing disorders, of Formula (I), wherein said disordersbeing selected from asthma, multiple sclerosis, artherosclerosis, andrheumatoid arthritis.

In another embodiment, the present invention is directed to a method fortreating or preventing rheumatoid arthritis, comprising administering toa patient in need thereof a therapeutically effective amount of acompound of Formula (I).

In another embodiment, the present invention is directed to a method fortreating or preventing multiple sclerosis, comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof Formula (I).

In another embodiment, the present invention is directed to a method fortreating or preventing atherosclerosis, comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof Formula (I).

In another embodiment, the present invention is directed to a method fortreating or preventing asthma, comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method fortreating or preventing inflammatory diseases, comprising administeringto a patient in need thereof a therapeutically effective amount of acompound of Formula (I).

In another embodiment, the present invention is directed to a method formodulation of CCR2 activity comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, Z is —C(O)—.

In another embodiment, X is —CHR¹⁶NR¹⁷—; and

-   R¹⁶ is selected from H, C₁₋₄ alkyl substituted with 0-1 R^(16a),    wherein the alkyl is selected from methyl, ethyl, propyl, i-propyl,    butyl, i-butyl, and s-butyl, and C₃₋₄ cycloalkyl substituted with    0-3 R¹⁶a wherein the cycloalkyl is selected from cyclopropyl and    cyclobutyl;-   R^(16a) is selected from methyl, ethyl, propyl, i-propyl, —OH, —SH,    —NR^(16c)R^(16c), —C(O)NR^(16c)R^(16c), and —NHC(O)R^(16c); and-   R¹⁷ is selected from H, methyl, ethyl, propyl, and i-propyl.

In another embodiment, R⁷, R⁸, R⁹, and R¹¹ are H;

-   R¹⁰ is selected from H and methyl;-   R¹⁶ is selected from H and methyl;-   R¹⁷ is selected from H and methyl;-   m is 0 or 1; and-   l is 0 or 1.

In another embodiment, R³ is selected from (CRR)_(q)OH, (CRR)_(q)SH,(CRR)_(q)OR^(3d), (CRR)_(q)S(O)_(p)R^(3d), (CRR)_(r)C(O)R^(3b),(CRR)_(q)NR^(3a)R^(3a), (CRR)_(r)C(O)NR^(3a)R^(3a),(CRR)_(r)C(O)NR^(3a)OR^(3d), (CRR)_(q)SO₂NR^(3a)R^(3a),(CRR)_(r)C(O)OR^(3d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substitutedwith 0-5 R^(3e), and a (CRR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(3e) wherein the heterocyclic system is selected from pyridinyl,thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl,isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl,1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl;

-   alternatively, R³ and R¹² join to form a C₃₋₆ cycloalkyl substituted    with 0-2 R^(3g) a C₅₋₆ lactam substituted with 0-2 R^(3g), or a C₅₋₆    lactone substituted with 0-2 R^(3g).

In another embodiment, R³ is selected from (CRR)_(q)OH, (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)NR^(3a)R^(3a), (CHR)_(r)C(O)NR^(3a)OR^(3d),(CH₂)C(O)R^(3b), (CH₂)_(r)C(O)OR^(3d), and (CH₂)-phenyl.

In another embodiment, R³ is H and R⁶, is selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(6d),(CRR)_(q)S(O)_(p)R^(6d), (CRR)_(r)C(O)R^(6b), (CRR)_(r)NR^(6a)R^(6a),(CRR)_(r)C(O)NR^(6a)R^(6a), (CRR)_(r)C(O)NR^(6a)OR^(6d),(CRR)SO₂NR^(6a)R^(6a), (CRR)_(r)C(O)OR^(6d), a (CRR)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(6e), and a (CRR)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(6e).

In another embodiment, R⁶ is selected from H, (CRR)_(q)OH, (CRR)_(q)SH,(CRR)_(q)OR^(6d), (CRR)_(q)S(O)_(p)R^(6d), (CRR)_(r)C(O)R^(6b),(CRR)_(q)NR^(6a)R^(6a), (CRR)_(r)C(O)NR^(6a)R^(6a),(CRR)_(r)C(O)NR^(6a)OR^(6d), (CRR)_(q)SO₂NR^(6a)R^(6a),(CRR)_(r)C(O)OR^(6d), a (CRR)_(r)—C₆₋₁₀ carbocyclic residue substitutedwith 0-5 R^(6e), and a (CRR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-6 R^(6e) wherein the heterocyclic system is selected from pyridinyl,thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl,isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl,1,2,6-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl.

In another embodiment, R¹ is selected from phenyl substituted with 0-3R⁴ and a 5-10 membered heteroaryl system substituted with 0-3 R⁴,wherein the heteroaryl is selected from benzimidazolyl, benzofuranyl,benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinylisothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,thiazolyl, thienyl, and tetrazolyl.

In another embodiment, R¹ is selected from phenyl substituted with 0-2R⁴, indolyl, and pyridyl.

In another embodiment, R² is selected from phenyl substituted with 0-3R⁵ and a 5-10 membered heteroaryl system containing 1-4 heteroatomssubstituted with 0-3 R⁵, wherein the heteroaryl system is selected frombenzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl, imidazolyl,indazolyl, indolyl, isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl,pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and tetrazolyl.

In another embodiment, R² is phenyl substituted with 0-2 R⁵.

In another embodiment, R⁴, at each occurrence, is selected from C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CR′R′)_(r)C₃₋₆ cycloalkyl, Cl, Br,I, F, NO₂, CN, (CR′R′)_(r)NR^(4a)R^(4a), (CR′R′)_(r)OH,(CR′R′)_(r)OR^(4d), (CR′R′)_(r)SH, (CR′R′)_(r)SR^(4d),(CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)R^(4b), (CR′R′)_(r)C(O)NR^(4a)R^(4a),(CR′R′)_(r)NR^(4f)C(O)R^(4b), (CR′R′)_(r)C(O)OR^(4d),(CR′R′)_(r)OC(O)R^(4b), (CR′R′)_(r)NR^(4f)C(O)OR^(4d),(CR′R′)_(r)OC(O)NR^(4a)R^(4a), (CR′R′)_(r)NR^(4a)C(O)NR^(4a)R^(4a),(CR′R′)_(r)S(O)_(p)R^(4b), (CR′R′)_(r)S(O)₂NR^(4a)R^(4a),(CR′R′)_(r)NR^(4f)S(O)₂R^(4b), (CR′R′)_(r)NR^(4f)S(O)₂ NR^(4a)R^(4a),C₁₋₆ haloalkyl, and (CR′R′)_(r)phenyl substituted with 0-3 R^(4e);

-   alternatively, two R⁴ on adjacent atoms join to form —O—(CH₂)—O—;-   R^(4a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl,    pentyl, hexyl, allyl, propargyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic    residue selected from cyclopropyl, cyclobutyl, cyclopentyl and    cyclohexyl;-   R^(4b), at each occurrence, is selected from methyl, ethyl, propyl,    i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl, allyl,    propargyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3    R^(4e), wherein the carbocyclic residue is selected from    cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and a    (CH₂)_(r)—S-6 membered heterocyclic system containing 1-4    heteroatoms selected from N, O, and S, substituted with 0-2 R^(4e),    wherein the heterocyclic system is selected from pyridinyl,    thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,    benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl,    quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl,    isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl,    1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl,    thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl;-   R^(4d), at each occurrence, is selected from H, methyl, CF₃, ethyl,    propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl,    allyl, propargyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue selected    from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;-   R^(4e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(4f)R^(4f), and (CH₂)_(r)phenyl;-   R^(4f), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, and cyclopropyl, cyclobutyl, and phenyl.

In another embodiment, R⁴ is selected from methyl, ethyl, propyl,i-propyl, butyl, ethylene, OCH₃, OCF₃, SCH₃, SO₂CH₃, Cl, F, Br, and CN;

-   alternatively, two R⁴ join to form —O—(CH₂)—O—.

In another embodiment, R⁵, at each occurrence, is selected from methyl,ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, t-butyl, pentyl,hexyl, (CR′R′)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CR′R′)_(r)NR^(5a)R^(5a), (CR′R′)_(r)OH, (CR′R″)_(r)OR^(5d),(CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)SR^(5d), (CR′R′)_(r)C(O)OH,(CR′R′)_(r)C(O)R^(5b), (CR′R′)_(r)C(O)NR^(5a)R^(5a),(CR′R′)_(r)NR^(5f)C(O)R^(5b), (CR′R′)_(r)C(O)OR^(5d),(CR′R′)_(r)OC(O)R^(5b), (CR′R′)_(r)NR^(5f)C(O)OR^(5d),(CR′R′)_(r)OC(O)NR^(5a)R^(5a), (CR′R′)_(r)NR^(5a)C (O)NR^(5a)R^(5a),(CR′R′)_(r)NR^(7a)C(O)NR^(7a)R^(7a),(CR′R′)_(r)NR^(7a)C(O)O(CRR′)_(r)R^(7d), (CR′R′)_(r)S(O)_(p)R^(5b),(CR′R′)_(r)S(O)₂NR^(5a)R^(5a), (CR′R′)_(r)NR^(5f)S(O)₂R^(5b), C₁₋₆haloalkyl, and (CHR′)_(r)phenyl substituted with 0-3 R^(5e);

-   alternatively, two R⁵ on adjacent atoms join to form —O— (CH₂)—O—;-   R^(5a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl,    pentyl, hexyl, allyl, propargyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic    residue selected from cyclopropyl, cyclobutyl, cyclopentyl and    cyclohexyl;-   R^(5b), at each occurrence, is selected from methyl, ethyl, propyl,    i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl, allyl,    propargyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue selected from    cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;-   R^(5d), at each occurrence, is selected from H, methyl, CF₃, ethyl,    propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl,    allyl, propargyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue selected    from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;-   R^(5e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(4f)R^(4f), and (CH₂)_(r)phenyl; and-   R^(5f), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, and cyclopropyl, cyclobutyl, and phenyl.

In another embodiment, R⁵ is selected from methyl, ethyl, propyl,i-propyl, butyl, i-butyl, s-butyl, pentyl, hexyl, CF₃, CF₂CF₃, CF₂H,OCF₃, Cl, Br, I, F, SCF₃, NR^(5a)R^(5a), NHC(O)OR^(5a), NHC(O)R^(5b),and NHC(O)NHR^(5a).

The invention may be embodied in other specific forms without departingfrom the spirit or essential attributes thereof. This invention alsoencompasses all combinations of preferred aspects of the invention notedherein. It is understood that any and all embodiments of the presentinvention may be taken in conjunction with any other embodiment todescribe additional even more preferred embodiments of the presentinvention. Furthermore, any elements of an embodiment are meant to becombined with any and all other elements from any of the embodiments todescribe additional embodiments.

Definitions

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom or ring is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalency is not exceeded, and that the substitution results in a stablecompound. When a substitent is keto (i.e., ═O), then 2 hydrogens on theatom are replaced.

When any variable (e.g., R^(a)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R^(a), then saidgroup may optionally be substituted with up to two R^(a) groups andR^(a) at each occurrence is selected independently from the definitionof R^(a). Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “C₁₋₈ alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, examples of which include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, and hexyl. C₁₋₈ alkyl, is intended toinclude C₁, C₂, C₃, C₄, C₅, C₆, C₇, and C₈ alkyl groups. “Alkenyl” isintended to include hydrocarbon chains of either a straight or branchedconfiguration and one or more unsaturated carbon-carbon bonds which mayoccur in any stable point along the chain, such as ethenyl, propenyl,and the like. “Alkynyl” is intended to include hydrocarbon chains ofeither a straight or branched configuration and one or more unsaturatedtriple carbon-carbon bonds which may occur in any stable point along thechain, such as ethynyl, propynyl, and the like. “C₃₋₆ cycloalkyl” isintended to include saturated ring groups having the specified number ofcarbon atoms in the ring, including mono-, bi-, or poly-cyclic ringsystems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl in the case of C₇ cycloalkyl. C₃₋₆ cycloalkyl, is intendedto include C₃, C₄, C₅, and C₆ cycloalkyl groups

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, for example CF₃,having the specified number of carbon atoms, substituted with 1 or morehalogen (for example —C_(v)F_(w) where v 1 to 3 and w=1 to (2v+1)).

As used herein, the term “5-6-membered cyclic ketal” is intended to mean2,2-disubstituted 1,3-dioxolane or 2,2-disubstituted 1,3-dioxane andtheir derivatives.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7,8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which maybe saturated, partially unsaturated, or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,;[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” or “heterocyclic system” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated,partially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, NH, O and S and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring. The nitrogen and sulfur heteroatoms may optionally beoxidized. The heterocyclic ring may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. If specificallynoted, a nitrogen in the heterocycle may optionally be quaternized. Itis preferred that when the total number of S and O atoms in theheterocycle exceeds 1, then these heteroatoms are not adjacent to oneanother. As used herein, the term “aromatic heterocyclic system” or“heteroaryl” is intended to mean a stable 5- to 7-membered monocyclic orbicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring whichconsists of carbon atoms and from 1 to 4 heterotams independentlyselected from the group consisting of N, O and S and is aromatic innature.

Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 4-piperidonyl,4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, tetrazolyl, and xanthenyl. In another aspect of theinvention, the heterocycles include, but are not limited to, pyridinyl,thiophenyl, furanyl, indazolyl, azetidinyl, benzothiazolyl,benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl,indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, morphlinyl,piperidinyl, pyrrolyl, 2,5-dihydropyrrolyl, pyrrazolyl, 1,2,4-triazolyl,1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

Examples of heteroaryls are 1H-indazole, 2H,6H-1,5,2-dithiazinyl,4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole; pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, tetrazolyl, and xanthenyl. In another aspect of theinvention, examples of heteroaryls are benzimidazolyl, benzofuranyl,benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinylisothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,thiazolyl, thienyl, and tetrazolyl.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.. . . ) the compounds of the present invention may be delivered inprodrug form. Thus, the present invention is intended to cover prodrugsof the presently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers which release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate derivatives of alcoholand amine functional groups in the compounds of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended toembody stable compounds.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention alone or in combination with otheractive ingredients effective to inhibit MCP-1 or effective to treat orprevent inflammatory disorders.

Synthesis

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety herein by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and work up procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents which are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used. This will sometimesrequire a judgment to modify the order of the synthetic steps or toselect one particular process scheme over another in order to obtain adesired compound of the invention. It will also be recognized thatanother major consideration in the planning of any synthetic route inthis field is the judicious choice of the protecting group used forprotection of the reactive functional groups present in the compoundsdescribed in this invention. An authoritative account describing themany alternatives to the trained practitioner is Greene and Wuts(Protective Groups In Organic Synthesis, Wiley and Sons, 1999).

Compounds of formula 1.5 are available as shown in Scheme 1. Adifferentially protected diamine 1.1 is singly deprotected and coupledwith a carboxylic acid 1.2 to provide the amide 1.3. For substrates withacid sensitive groups at R³ (i.e. tert-butyl esters or ethers), aselective removal of the N-Boc group is still readily achieved (Frank S.Gibson, et al, J. Org. Chem. 1994, 59, 3216). If the central spacer isan α-amino acid, than a more optimal protocol involves stepwise couplingas shown (1.1→1.6→1.3). The other terminus of the diamine subunit of 1.3is revealed by hydrogenation, and the nascent amine is readilyconjugated with aldehydes 1.7 (R¹⁶=H) and ketones 1.7 under reductiveconditions (MeOH, NaCNBH₃ or THF, AcOH, NaHB(OAc)₃) to provide thedesired secondary amine 1.5. The chemistry shown in Scheme 1 is quitegeneral, and a wide array of amino acids 1.8, amino acid conjugates 1.2,aldehydes 1.7 (R¹⁶=H), and ketones 1.7 are commercially available. Thus,the primary challenge in producing compounds of formula 1.5 lies in thesynthesis of the differentially protected diamines 1.1. Accordingly, thesyntheses of a number of important representative embodiments of 1.1 areillustrated in Schemes 2-15.

Singly substituted variants of 1.1 (R³≠H) are readily available as shownin Scheme 2. Compounds of formula 2.1—namely L- or D-N_(α)-Boc,N_(ω)-Cbz-diaminopropionic acid, diaminobutyric acid, and ornithine—arecommercially available and are readily converted into esters 2.2 andamides 2.3 using a number of standard synthetic methods (two of whichare illustrated). It is possible to synthesize a wide variety of othersingly substituted variants of 1.1 (R³≠H or C(O)X) from L- or D-α, β, orγ-amino acids 2.4. The α-amino acids are available from commercialsources, and the β- and γ-amino acids are readily prepared from theα-amino acids (Tobias Hintermann, et al., Helv. Chim. Acta. 1998, 81,983). Selective reduction of the carboxylic acid of 2.5 to the alcoholin the presence of other sensitive functionality (e.g. esters) isaccomplished by initial conversion of the acid to the succinimide ester,followed by low temperature reduction (NaBH₄, EtOH, 0° C., 5 min).Simple transformation of the alcohol to the azide via the mesylateprovides 2.5.

Doubly substituted variants of 1.1 (R³, R¹²≠H) are available as shown inSchemes 3 and 4. The methodology for the synthesis of L- andD-α-alkylserines 3.1 has been described in the literature (DieterSeebach and Johannes Aebi, Tetrahedron Lett. 1984, 25, 2545). Sequentialfunctionalization of the amine, acid, and alcohol functionalitiesaffords mesylate 3.2. This mesylate can be reacted with either sodiumazide to give the masked α, β-diamine 3.3 or with sodium cyanide to givenitrile 3.4. Hydrogenation of 3.4 and protection of the resultant amineaffords protected α, γ-diamine 3.5, which is easily converted into theamide 3.6 if desired. Alternatively, 3.1 can be doubly homologated usingstandard chemistry to give 3.8 via the intermediacy of the unsaturatedester 3.7. Note that this sequence (3.1→3.7→3.8) capitalizes on thepresence of the R¹² group to modulate the reactivity of the estertowards bases and reducing agents. Displacement of the mesylate of 3.8with sodium azide affords the selectively protected α, β-diamine 3.9,which can be subsequently transformed to the amide 3.10 if desired.

It is possible to synthesize a wide variety of other doubly substitutedvariants of 1.1 (R³, R¹²≠H; R³≠C(O)X) from L- or D-α-alkyl-α-, β-, orγ-amino acids 4.1 (Scheme 4) using the same methodology that wasdescribed above for the sequence shown in Scheme 2 (2.4→2.5). Theenantioselective synthesis of α-alkyl-α-amino acids 4.1 (l=m=0) has beendescribed by a number of authors (cf. André Charette and ChristopheMellon, Tetrahedron 1998, 54, 10525 for leading references). Thesecompounds can be readily transformed into the β- and γ-homologues of 4.1(l=1, m=0 and 1=m=1, respectively) using the same chemistry that hasbeen described for α-unsubstituted-α-amino acids (Tobias Hintermann, etal., Helv. Chim. Acta. 1998, 81, 983) as shown in the lower portion ofScheme 4.

Doubly substituted variants of 1.1 (R³≠H, R⁶ or R¹⁰≠H) are available asshown in Schemes 5 and 6. A variety of syn β-hydroxy-β-amino acids 5.1are available in homochiral form from either commercial sources (R⁶=Me)or by synthesis (cf. Adam J. Morgan, et al., Org. Lett. 1999, 1, 1949for leading references). Protection of the amine group as its tert-butylcarbamate is followed by standard amide formation to afford 5.2.Installation of the second protected amine functionality may beaccomplished using either Mitsonobu chemistry (illustrated) or a moreconventional approach (Ms₂O; then NaN₃) to afford the antiβ-azido-α-amino amide 5.3. If the syn isomer of the β-azido-α-aminoamide 5.3 is desired, than the stereochemistry of the β-hydroxyl groupof 5.2 can be inverted (p-NO₂PhCO₂H, Ph₃P, DEAD; then LiOH) beforeinstallation of the azide. Either isomer of the amide 5.3 can be readilyconverted to the ester via methanolysis of the imide derivative (D. L.Flynn, et al., J. Org. Chem. 1983, 48, 2424). The γ- and γ-homologues of5.4 are synthesized from a different starting material, namely theβ-alkyl-γ-hydroxy-α-amino ester 5.5, which is available via thealkylation of suitably protected aspartic acid derivatives (Jean-PierreWolf and Henry Rapoport, J. Org. Chem. 1989, 54, 3164). The mesylatederivative of 5.5 is displaced with sodium azide or with sodium cyanide;both of these products may then be hydrogenated and then treated withacid to give the α, γ- and α, δ-diamino acids 5.6 and 5.11. Selectiveprotection of the terminal amine of either 5.6 or 5.11 is accomplishedafter initial treatment with Cu(II) (Andre Rosowsky and Joel E. Wright,J. Org. Chem. 1983, 48, 1539). Subsequent protection of the α-amine,decomplexation of the copper with EDTA, and amidation or esterificationof the carboxylic acid provides access to any of the final products 5.8,5.9, 5.13, or 5.14.

It is possible to synthesize a wide variety of other doubly substitutedvariants of 1.1 (R⁶ or R¹⁰≠H; R³≠H or C(O)X) from α-amino acids as shownin Scheme 6. Formation of the α-amino ketone 6.2 from the α-amino acid6.1 is easily accomplished via Grignard addition to the α-amino Weinrebamide. The ketone 6.2 is reduced to the alcohol and reacted with mesylanhyrdide to give the secondary mesylate 6.3. This mesylate is reactedwith either sodium azide to afford the masked α, β-diamine 6.4, or withsodium cyanide to give nitrile 6.5. The nitrile is readily reduced andprotected to provide the protected α, γ-diamine 6.6. Alternatively, theketone 6.2 may be homologated under standard Horner-Wadsworth-Emmonsconditions to give the unsaturated ester, which may then be reduced tothe saturated acid 6.7. This acid is readily converted to the protectedα, δ-diamine 6.9 using the same methodology that was described above forthe sequence shown in Scheme 2 (2.4→2.5).

Doubly substituted variants of 1.1 (R⁶ or R⁸≠H; R³≠H) are available asshown in Schemes 7 and 8. Any diastereomer of the carboxylic acid 7.1 isavailable from the alkylation of a suitably protected glutamic acidderivative (Zong-Qiang Tian, et al, J. Org. Chem. 1997, 62, 514). Theacid of 7.1 is converted into a carbamate-protected amine using aCurtius rearrangement; subsequent deprotection of the pthalimideprotecting group gives the monoprotected α, γ-diamine 7.2. Acid-mediatedcleavage of the tert-butyl ester can be followed by N-Boc protection togive the acid 7.3, which may be readily transformed into either theamide 7.4 or the methyl ester 7.5. Alternatively, the key intermediate7.1 can be converted into the azide 7.6 using the same methodology thatwas described above for the sequence shown in Scheme 2 (2.4→2.5).Appropriate protecting group manipulation would then afford the maskedα, δ-diamino acid 7.7, which can be converted into the amide 7.8 or theester 7.9 using standard chemistry.

It is possible to synthesize a wide variety of other doubly substitutedvariants of 1.1 (R⁶ or R⁸≠H; R³≠H or C(O)X) from β-amino acids as shownin Scheme 8. Conversion of the readily available (cf. David A. Evans, etal., J. Org. Chem. 1999, 64, 6411 for leading references) carboxylicacid 8.1 to the aldehyde may be accomplished under mild conditions (T.Fukuyama, et al., J. Am. Chem. Soc. 1990, 112, 7050) such that any esterfunctionality in R is not affected. Reaction of the resultant aldehydewith a single equivalent of Grignard reagent at low temperature affordsthe secondary alcohol 8.2. The key alcohol 8.2 can be converted into theγ-azido amine 8.3 or the nitrile 8.4; the latter is readily transformedinto the protected α, δ-diamine 8.5 via hydrogenation and N-protection.

Doubly substituted variants of 1.1 (R³, R⁶≠H) are available as shown inSchemes 9 and 10. Pyrroglutamic acid 9.1, which is commerciallyavailable in either antipode, may be N-protected and C-amidated to give9.2. Reaction of 9.2 with a Grignard reagent gives the ketone (TomihisaOhta, et al., Chem. Lett. 1987, 2091), which may be reduced to give thealcohol 9.3. Conversion of the alcohol to the azide provides the maskedα, δ-diamine 9.4. If desired, the amide of 9.4 may be saponified to give9.5 via the imide (David A. Evans, et al., Tetrahedron Lett. 1997, 38,4535); the nascent acid is easily transformed into the ester 9.7 oranother amide 9.6 using standard chemistry.

It is possible to synthesize a wide variety of other doubly substitutedvariants of 1.1 (R⁶≠H; R³≠H or C(O)X) from γ-amino acids as shown inScheme 10. Conversion of the readily available (Tobias Hintermann, etal., Helv. Chim. Acta. 1998, 81, 983) carboxylic acid 10.1 to thealdehyde may be accomplished under mild conditions. Reaction of thealdehyde with a single equivalent of Grignard reagent at low temperaturewould then afford the secondary alcohol, which can be readilytransformed into the masked α, δ-diamine 10.3 using Mitsonobu chemistry.

Schemes 2-10 have illustrated how to prepare a number of doublysubstituted variants of 1.1 (R³≠H; R³=C(O)X or R³≠C(O)X) in a regio- andstereoselective fashion. Given this instruction, it will be apparent toone skilled in the art of organic synthesis how to prepare the analogoustriply substituted variants of 1.1 using the appropriate combination ofthe chemistry presented in Schemes 2-10.

Singly, doubly, and triply substituted variants of 1.1 (R³=C(O)X) can beconverted into other variants of 1.1 that contain a hydroxylfunctionality as shown in Scheme 11. Carboxylic acids of formula 11.1are available as shown in Schemes 2-10; if the synthesis of only themethyl ester has been illustrated, than the methyl ester may beconverted into the acid 11.1 via saponification (LiOH, THF/MeOH/H₂O).Conversion of the acid into the Weinreb amide and reaction with aGrignard reagent provides ketone 11.3. This ketone may either be reactedwith another Grignard reagent (R=R or R≠R) to afford the tertiaryalcohol 11.4 or reduced with sodium borohydride (or other reducingagent) to provide the secondary alcohol 11.5. If desired, the alcoholcould be further transformed to provide 11.6.

Varients of protected diamine 1.1 that contain a spirocyclic group (R³and R¹² conjugated in a ring) are available as shown in Schemes 12-15.Cyclic ketone 12.1 is converted into the α-amino nitrile 12.2 usingclassical Strecker chemistry (T. A. Keating and R. W. Armstrong, J. Am.Chem. Soc. 1996, 118, 2574). Under certain circumstances, this amine maybe incorporated directly into the chemistry shown in Scheme 1 (cf.Example 39); alternatively, the amine can be protected, the nitrilehydrogenated, and the nascent amine protected to give the doublyprotected α, β-diamine 12.3. The ketone 12.1 may also be homologatedusing a Hornor-Wadsworth-Emmons reaction to provide enoate 12.4, whichis readily reacted with ammonia and then protected to afford the keyβ-amino ester 12.5. This intermediate can be converted into theprotected α, β-diamine via ester saponification and Curtiusrearrangement. Alternatively, the ester of 12.5 may be reduced, and theresultant primary alcohol derivatized as the mesylate to afford 12.6.The mesylate 12.6 may be reacted with sodium azide (DMSO, heat) to givethe masked α, γ-diamine 12.7. Alternatively, the mesylate 12.6 may bereacted with sodium cyanide to give the nitrile, which may then behydrogenated and reacted with dibenzyl carbonate to give the protectedα, δ-diamine 12.8.

The preparation of the two key intermediates for the synthesis of thetarget compounds 14.5, 14.7, 15.3, and 15.5 (all variants of 1.1) isshown in Scheme 13. Trapping of the enolate derived from 13.1 with analkyl bromide containing a pendant olefin affords compound 13.2 (DieterSeebach and Johannes Aebi, Tetrahedron Lett. 1984, 25, 2545). Hydrolysisof 13.2 with refluxing 6N HCl, followed by N-protection with tert-butyldicarbonate affords the β-hydroxy acid 13.4. This latter compound isreadily functionalized to provide the fully protected synthon 13.6,which may be utilized in the chemistry described in Scheme 14.Alternatively, the enolate of 13.1 can be reacted with a diiodoalkane;the resultant primary iodide is readily displaced with sodium azide togive 13.3 (for highly analogous chemistry, cf. Amos B. Smith, III, etal., Tetrahedron Lett. 1997, 38, 3809). The primary azide 13.3 may betransformed into the fully protected synthon 13.7 using the chemistrydescribed above; this compound is ready for incorporation into Scheme15. If desired, the enantiomer of 13.1 may be synthesized from D-serineand utilized in Scheme 13 to afford the enantiomers of 13.6 and 13.7.

Varients of protected diamine 1.1 that contain an oxygenated spirocyclicgroup (R³ and R¹² conjugated in a ring) are available as shown in Scheme14. Oxidation of the terminal olefin of 13.6 to the corresponding methylester 14.1 may be achieved using known chemistry (David A. Evans andEric B. Sjogren, Tetrahedron Lett. 1986, 27, 4961). Dieckman cyclizationof the diester 14.1 under basic conditions provides the β-ketoester14.2. If desired, the β-ketoester may be alkylated under mild conditions(carbonate, alkyl iodide); the resultant product and its precursor mayboth be transformed into ketones 14.3 (R^(3g)≠H and R^(3g)=H,respectively) by saponification and decarboxylation. Compounds offormula 14.3 are readily reduced and deprotected to give the diol; theprimary alcohol can be derivatized selectively in the presence of thesecondary alcohol through the use of tosyl chloride under carefullycontrolled conditions (pyridine, 0° C.). The resultant lynchpin tosylate14.4 may be reacted with sodium azide to afford the masked α, β-diamine14.5. Alternatively, the tosylate of 14.4 may be displaced with sodiumcyanide; reduction of the resultant nitrile and protection of thenascent amine affords the protectd α, γ-diamine 14.7.

Varients of protected diamine 1.1 that contain a spirocyclic lactam (R³and R¹² conjugated into a lactam) are available as shown in Scheme 15.Saponification of the methyl ester of 13.7, followed by hydrogenolysisof the azide provides the amino acid 15.1 (R^(3g)=H). If desired, thisamine may be monoalkylated under reductive amination conditions to givethe N-alkylated amino acid 15.1 (R^(3g)≠H). Cyclization of the aminoacid using DCC affords lactam 15.2, which is readily deprotected andtosylated to afford the key intermediate 15.4. The tosylate 15.3 may bereacted with sodium azide to afford the masked α, β-diamine 15.4.Alternatively, the tosylate of 15.4 may be displaced with sodiumcyanide; reduction of the resultant nitrile and protection of thenascent amine affords the protectd α, γ-diamine 15.5. One skilled in theart will readily appreciate that the lactone analogs of compounds 15.4and 15.5 can be synthesized by using similar chemistry, allowing for achange in the electrophile in Scheme 13.

As will be apparent to one skilled in the art, the instruction givenabove (Schemes 2-15) on the synthesis of embodiments of 1.1 usuallyprovides for the synthesis of enantiomerically pure material, but notnecessarily diastereomerically pure material. When required, separationof racemic material can be achieved by HPLC using a chiral column or bya resolution using a resolving agent such as camphonic chloride (StevenD. Young, et al, Antimicrobial Agents and Chemotheraphy 1995, 2602).Likewise, separation of diastereomers of target compounds can beachieved by HPLC using either an achiral or chiral column. If desired,alcohol diastereomers may be readily interconverted using Mitsonobuconditions (p-NO₂PhCO₂H, Ph₃P, DEAD). If a particular alcoholdiastereomer is preferred, the precursor ketone can be reduced using achiral reducing agent (e.g. E. J. Corey and Christopher J. Helal, Angew.Chem. Int. Ed. 1998, 37, 1986) in order to favor the production of onediastereomer over the other. A number of the variants of the targetcompounds of formula 1.5 may be elaborated into other desirablecompounds as shown in Schemes 16-19. In the specific instance ofcompounds of formula 16.1, the ester may either be reduced or hydrolyzedto give the alcohol 16.4 or the acid 16.2, respectively. The carboxylicacid 16.2 may be coupled with amines without significant epimerizationusing HATU to afford the amide 16.3.

The chemistry described in Scheme 16 is not readily applied to themainchain homologs of 16.1. The mainchain homologs of amide 16.3 aremost easily prepared from the amidated diamine variants of 1.1 (cf.Schemes 2, 3, 5, 7, and 9). For the mainchain homologs of alcohol 16.4,the alternative strategy shown in Scheme 17 must be utilized. Compoundsof formula 17.1, which still have one nitrogen of the core diamine inprotected form, may be reduced with sodium borohydride to give alcohol17.2. Hydrogenation of 17.2 affords the free amine 17.4, which isalkylated readily under reductive conditions to give 17.6. If desired,the mainchain homologs of carboxylic acid 16.2 may be prepared usinganalogous chemistry, except that the ester of 17.1 is saponified to givethe corresponding carboxylic acid 17.3 before being hydrogenated andalkylated to give 17.7.

The chemistry described in Scheme 16 is not readily applied to thesidechain homologs of 16.1, and so the alternative strategy shown inScheme 18 must be utilized. Compounds of formula 18.1, which still haveone nitrogen of the core diamine in protected form, may be deprotectedwith TFA and amidated under standard conditions to provide compounds offormula 18.2. These are then hydrogenated and alkylated to afford thedesired compounds of formula 18.4.

If desired, the compounds of formulas 19.1 and 19.3, both specificembodiements of formula 1.5, may be further transformed as shown inScheme 19. Selective N-protection of the secondary nitrogen of either19.1 or 19.3 under biphasic conditions is followed by Dess-Martinoxidation of the alcohol and deprotection of the benzyl carbamate toprovide the amino ketones 19.1 and 19.4.

Because the primary amide is a preferred R³ substituent for compounds offormula 1.5, it is also possible to synthesize compounds of formula 20.8using solid-phase chemistry. The protecting group strategy for thediamino acids 20.1 is different than that utilized in Scheme 1. Therequisite N_(α)-Fmoc, N_(ω)-Alloc diamino acids are available fromeither commercial sources (e.g. N_(α)-Fmoc, N_(ω)-Alloc diaminopropionicacid, diaminobutyric acid, and ornithine) or by synthesis from theintermediates described in Schemes 3, 5, 7, and 9. The straightforwardfour-step conversion of these intermediates 11.1 into the suitablyprotected N_(α)-Fmoc, N_(ω)-Alloc diamino acids 20.1 is illustrated inScheme 21 for the sake of clarity.

Once obtained, compounds of formula 20.1 may be attached to anappropriate amine resin (e.g. Rink or PAL), deprotected, coupled withamino acids 20.3, deprotected, and coupled with carboxylic acids 20.5 togive the resin bound polyamide 20.6. If desired, this sequence(20.1→20.2→20.4→20.6) may be performed on an automated peptidesynthesizer. Deprotection of the N_(ω)-Alloc group using Pd(PPh₃)₄ andN-methyl morpholine is followed by reductive amination of theresin-bound amine (Jeremy Green, J. Org. Chem. 1995, 60, 4287).Liberation of the desired primary amide 20.8 from the resin isaccomplished via treatment with 5% Et₃SiH/TFA. It is apparent to oneskilled in the art of organic synthesis that large compound libraries(>100 compounds) can be prepared using this chemistry, given the widevariety of N_(α)-Fmoc amino acids 20.3, carboxylic acids 20.5, andaldehydes 20.7 that are available from commercial sources and bysynthesis.

Because N-alkyl- and N,N-alkylamides are preferred R³ substituents forcompounds of formula 1.5, it is also possible to synthesize compounds offormula 22.5 using solid-phase chemistry, as shown in Scheme 22. In thisinstance, the chemistry is highly analogous to that described above forScheme 21. The only differences come in the resin-loading step(21.1→22.1), and the resin-release step (22.4→22.5), both of which areperformed according to the protocols of Ellman (Bradley J. Backes andJonathon A. Ellman, J. Org. Chem. 1999, 64, 2322). It is apparent to oneskilled in the art of organic synthesis that large compound libraries(>100 compounds) can be prepared using this chemistry, given the widevariety of N_(α)-Fmoc amino acids 20.3, carboxylic acids 20.5, aldehydes20.7, and amines that are available from commercial sources and bysynthesis.

As will be readily appreciated by one skilled in the art of organicsynthesis, there is an element of pseudosymmetry present in compounds offormula 1.1. Thus, one can synthesize more compounds of formula 1.5 thanare available from the reaction sequence shown in Scheme 1 withoutchanging the protecting group scheme of the many intermediates offormula 1.1, the syntheses of which have already been detailed inSchemes 2-15. As shown in Scheme 23, hydrogenation of 1.1 and couplingof the nascent amine with acid 1.2 provides amide 23.1. Alternatively,compounds of formula 23.1 may be accessed using a stepwise approach (cf.Scheme 23, 1.1→23.3→23.1). Acid-mediated removal of the N-Boc group from23.1 is followed by reductive amination to provide compounds of formula23.2. If one allows for a simple change in the designation of thesidechain R groups, than these compounds of formula 23.2 are actuallyembodiments of compounds of formula 1.5, as is clearly illustrated inScheme 23 (see also Example 35).

Finally, it should be noted that 1.5 and its various embodiments (e.g.16.3, 16.4, 17.6, 17.7, 18.4, 21.8, and 22.5) can be alkylatedselectively under reductive amination conditions to provide compounds24.1.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

Abbreviations used in the Examples are defined as follows: “1×” foronce, “2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq”for equivalent or equivalents, “g” for gram or grams, “mg” for milligramor milligrams, “mL” for milliliter or milliliters, “¹H” for proton, “h”for hour or hours, “M” for molar, “min” for minute or minutes, “MHz” formegahertz, “MS” for mass spectroscopy, “NMR” for nuclear magneticresonance spectroscopy, “rt” for room temperature, “tlc” for thin layerchromatography, “v/v” for volume to volume ratio. “α”, “β”, “R” and “S”are stereochemical designations familiar to those skilled in the art.

Example 1 Methyl(2S)-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate

(1a) tert-Butyl glycine hydrochloride (6.6 g, 50 mmol) was suspended inmethylene chloride and meta-trifluoromethyl benzoic acid (9.5 g, 50mmol) was added, followed by N,N-diisopropylethylamine (17.5 mL, 100mmol), EDC (10.2 g, 53 mmol), and DMAP (300 mg, 2.5 mmol). The reactionwas stirred for 12 hrs at RT and partitioned between EtOAc and 1 N HCl.The organic phase was washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The material was purified via flashchromatography to give tert-Butyl (3-trifluoromethylbenzoyl)glycine as aclear and colorless oil (12 g), which was dissolved in methylenechloride (40 mL), cooled to 0° C., and treated with trifluoroacetic acid(20 mL). The reaction was stirred for 3.5 hrs at RT and concentrated invacuo. The material was redissolved in methylene chloride andconcentrated again; this procedure was repeated three more times to givethe desired carboxylic acid 1.2 (Z=—C(O)—, R²=3-trifluoromethylphenyl,all other R=H, 8.9 g). ¹H-NMR (300 MHz): δ 8.03 (s, 1H), 7.94 (d, 1H,J=7.7 Hz), 7.66 (d, 1H, J=7.7 Hz), 7.48 (t, 1H, J=7.9 Hz), 4.08 (s, 2H).

(1b) A solution of (S)-N_(α)-Boc,N_(β)-Cbz-diaminopropionic acid DCHAsalt (S)-2.1 (l=m=0; 5.07 g, 9.77 mmol) in methylene chloride wastreated successively with EDC (1.96 g, 10.3 mmol) and methanol (0.79 mL,19.5 mmol). The reaction was stirred at RT for 4 hrs and partitionedbetween EtOAc and 1 N hydrochloric acid. The aqueous phase was extractedwith EtOAc (2×). The organic extracts were combined, washed with brine,dried (Na₂SO₄), filtered, and concentrated in vacuo. The material waspurifed by flash chromatography to give the desired ester (S)-2.2(l=m=0; 1.86 g). MS found: (M+Na)⁺=375.2.

(1c) The ester (S)-2.2 (l=m=0) was dissolved in methylene chloride (40mL), treated with trifluoroacetic acid (20 mL), and stirred at roomtemperature for 1.5 hrs before being concentrated in vacuo. The materialwas redissolved in methylene chloride and concentrated again; thisprocedure was repeated three more times to give the desired amine(quantitative). A solution of the amine (5.28 mmol) in methylenechloride was charged with carboxylic acid 1.2 (Z=—C(O)—,R²=3-trifluoromethylphenyl, all other R=H, 5.6 mmol), BOP (2.5 g, 5.7mmol), and N,N-diisopropylethylamine (2.1 mL, 12 mmol). The reaction wasstirred at RT for 12 hrs and partitioned between EtOAc and sat. NaHCO₃.The organic extracts were washed with brine, dried (Na₂SO₄), filtered,and concentrated in vacuo. The material was purifed by flashchromatography to give the desired amide (S)-1.3 (1=m=0, PGN=CbzHN,R³=CO₂Me, Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H, 2.01 g).MS found: (M+Na)⁺=504.2.

(1d) A solution of the amide (S)-1.3 (PGN=CbzHN, l=m=0, R³=CO₂Me,Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H, 0.25 g, 0.53 mmol)in methanol was charged with 5% Pd/C, Degussa type (ca. 0.1 g). Thevessel was purged with hydrogen and stirred under 1 atm of hydrogen for7 hrs before being filtered and concentrated in vacuo. This material wasdissolved in methanol and treated with 2,4-dimethylbenzaldehyde (0.09mL) and sodium cyanoborohydride (40 mg). The reaction was stirred for 12hrs at RT and quenched with sat. NaHCO₃. The resultant mixture wasextracted with EtOAc (2×). The organic extracts were combined, washedwith brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Thematerial was purifed by flash chromatography to give one pure fractionof the title compound (S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=CO₂Me,Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H; 20 mg). MS found:(M+H)⁺=466.3.

Example 2 Methyl(2R)-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate

(2a) (R)—N_(α)-Boc,N_(β)-Cbz-diaminopropionic acid DCHA salt (R)-2.1(l=m=0; 2.6 g, 5.07 mmol) was incorporated into the above procedure (1b)to give (R)-2.2 (l=m=0; 0.82 g), which was subsequently incorporatedinto procedures (1c) & (1d). Purification by RP-HPLC provided the titlecompound (R)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=CO₂Me, Z=—C(O)—,R²=3-trifluoromethylphenyl, all other R=H; 85 mg). MS found:(M+H)⁺=466.3.

Example 3(2S)-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoicacid

(3a) To a solution of ester (S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl,R³=CO₂Me, Z=—C(O)—, R²=3trifluoromethylphenyl, all other R=H; 40 mg) in2:2:1 THF:MeOH:H₂O was added LiOH (ca. 40 mg). The reaction was stirredat RT for 12 hrs, quenched with 1 N HCl and extracted with EtOAc (3×).The organic extracts were combined, washed with brine, dried (MgSO₄),filtered, and concentrated in vacuo. The material was purifed by reversephase HPLC to give the desired acid (S)-16.2 (R¹=2,4-dimethylphenyl,Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H; 29 mg). MS found:(M+H)⁺=452.3.

Example 4(2S)-N-Methyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(4a) To a solution of acid (S)-16.2 (R¹=2,4-dimethylphenyl,R²=3-trifluoromethylphenyl, all other R=H; 24 mg, 0.04 mmol) in 4:1methylene chloride/DMF was added methylamine hydrochloride (14 mg, 0.21mmol), N,N-diisopropylethylamine (0.05 mL, 0.29 mmol), and HATU (19 mg,0.05 mmol). The reaction was stirred for 12 hrs at RT and then filteredand concentrated in vacuo. The material was purified by reverse phaseHPLC to give the desired amide (S)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)NHMe, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H; 12 mg). Exact MS calcd for C₂₃H₂₈F₃N₄O₃, the formula for(M+H)⁺=465.2113. Found: 465.2114.

Example 5(2S)-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(5a) Ammonia (22 μL of a 2.0 M solution) was incorporated into the aboveprocedure (4a) to give the title amide (S)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)NH₂, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H, 5.0 mg). Exact MS calcd for C₂₂H₂₆F₃N₄O₃, the formula for(M+H)⁺451.1957. Found: 451.1958.

Example 6(2R)-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(6a) (S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R²=3-trifluoromethylphenyl,all other R=H; 60 mg) was incorporated into the above procedure (3a) togive (R)-16.2 (R¹=2,4-dimethylphenyl, Z=—C(O)—,R²=3-trifluoromethylphenyl, all other R=H; 55 mg). MS found:(M+H)⁺=452.3.

(6b) Ammonia (0.23 mL of a 2.0 M solution) and (R)-16.2(R¹=2,4-dimethylphenyl, R²=3-trifluoromethylphenyl, all other R=H; 52mg) were incorporated into the above procedure (4a) to give the titleamide (R)-16.3 (R¹=2,4-dimethylphenyl, —C(O)N(R^(3a))₂=—C(O)NH₂,Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H; 24 mg). Exact MScalcd for C₂₂H₂₆F₃N₄O₃, the formula for (M+H)⁺=451.1957. Found:451.1967.

Example 7(2S)-N-Ethyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(7a) Ethylamine (22 μL of a 2.0 M solution) was incorporated into theabove procedure (4a) to give the title amide (S)-16.3(R¹=2,4-dimethylphenyl, —C(O)N(R^(3a))₂=—C(O)NHEt, Z=—C(O)—,R²=3-trifluoromethylphenyl, all other R=H, 5.5 mg). Exact MS calcd forC₂₄H₃₀F₃N₄O₃, the formula for (M+H)⁺=479.2270. Found: 479.2266.

Example 8(2S)-N-Benzyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(8a) Benzyl amine (4.8 μL) was incorporated into the above procedure(4a) to give the title amide (S)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)NHBn, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H; 4.5 mg). Exact MS calcd for C₂₉H₃₂F₃N₄O₃, the formula for(M+H)⁺=541.2427. Found: 541.2431.

Example 9(2S)-N-Isopropyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(9a) Isopropylamine (3.8 μL) was incorporated into the above procedure(4a) to give the title amide (S)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)NHi-Pr, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H, 2.0 mg). Exact MS calcd for C₂₅H₃₂F₃N₄O₃, the formula for(M+H)⁺=493.2427. Found: 493.2450.

Example 10(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(10a) tert-Butylamine (40 μL) was incorporated into the above procedure(4a) to give the title amide (S)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)NHt-Bu, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H; 10 mg). Exact MS calcd for C₂₆H₃₄F₃N₄O₃, the formula for(M+H)⁺=507.2583. Found: 507.2577.

Example 11(2S)-N-Cyclopropyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(11a) Cyclopropylamine (40 μL) was incorporated into the above procedure(4a) to give the title amide (S)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)NHc-Pr, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H; 5 mg). Exact MS calcd for C₂₅H₃₀F₃N₄O₃, the formula for(M+H)⁺=491.2270. Found: 491.2260.

Example 12(2S)-N-Cyclobutyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(12a) Cyclobutylamine (50 μL) was incorporated into the above procedure(4a) to give the title amide (S)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)NHc-Bu, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H; 20 mg). Exact MS calcd for C₂₆H₃₂F₃N₄O₃, the formula for(M+H)⁺=505.2427. Found: 505.2430.

Example 13(2S)-N-Phenyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(13a) Aniline (4.0 μL) was incorporated into the above procedure (4a) togive the title amide (S)-16.3 (R¹ =2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)NHPh, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H, 1.3 mg). MS found: (M+H)⁺=527.3.

Example 14(2S)-N,N-Dimethyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(14a) N,N-Dimethyl amine (18.0 mg of the hydrochloride salt) wasincorporated into the above procedure (4a) to give the title amide(S)-16.3 (R¹=2,4-dimethylphenyl, —C(O)N(R^(3a))₂=—C(O)NMe₂, Z=—C(O)—,R²=3-trifluoromethylphenyl, all other R=H; 5 mg). Exact MS calcd forC₂₄H₃₀F₃N₄O₃, the formula for (M+H)⁺=479.2270. Found: 479.2267.

Example 15(2S)-N-Methyl,N-methoxy-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(15a) N,O-Dimethylhydroxylamine (17.5 mg of the hydrochloride salt) wasincorporated into the above procedure (4a) to give the title amide(S)-16.3 (R¹=2,4-dimethylphenyl, —C(O)N(R^(3a))₂=—C(O)N(OMe)Me,Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H; 20 mg). Exact MScalcd for C₂₄H₃₀F₃N₄O₄, the formula for (M+H)⁺=495.2219. Found:495.2230.

Example 16 Methyl(2S)-3-[[(4-chlorophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate

(16a) para-Chlorobenzaldehyde (71 mg, 0.51 mmol) was incorporated intothe above procedure (1d) to give the title ester (S)-1.5 (l=m=0,R¹=4-chlorophenyl, R³═CO₂Me, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H; 59 mg). Exact MS calcd for C₂₁H₂₂F₃Cl₁N₃O₄, the formula for(M+H)⁺=472.1251. Found: 472.1239.

Example 17(2S)-3-[[(4-chlorophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(17a) (S)-1.5 (l=m=0, R¹=4-chlorophenyl, R³=CO₂Me, Z=—C(O)—,R²=3-trifluoromethylphenyl, all other R=H; 51 mg, 0.09 mmol) wasincorporated into the above procedure (3a) to give the crude carboxylicacid (S)-16.2 (R¹=4-chlorophenyl, Z=—C(O)—, R²=3-trifluoromethylphenyl,all other R=H; 47 mg). This material was not characterized, but rathertaken directly into procedures (17b) and (18a).

(17b) Ammonia (0.2 mL of a 2.0 M solution) and (S)-16.2(R¹=4-chlorophenyl, Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H;23 mg) were incorporated into the above procedure (4a) to give the titleamide (S)-16.3 (R¹=4-chlorophenyl, —C(O)N(R^(3a))₂=—C(O)NH₂, Z=—C(O)—,R²=3-trifluoromethylphenyl, all other R=H, 6.5 mg). Exact MS calcd forC₂₀H₂₁Cl₁F₃N₄O₃, the formula for (M+H)⁺=457.1254. Found: 457.1257.

Example 18(2S)-N-Ethyl-3-[[(4-chlorophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(18a) Ethylamine (0.18 mL of a 2.0 M solution) and (S)-16.2(R¹=4-chlorophenyl, R²=3-trifluoromethylphenyl, all other R=H; 23 mg)were incorporated into the above procedure (4a) to give the title amide(S)-16.3 (R¹=4-chlorophenyl, —C(O)N(R^(3a))₂=—C(O)NHEt, Z=—C(O)—,R²=3-trifluoromethylphenyl, all other R=H, 7.0 mg). Exact MS calcd forC₂₂H₂₅Cl₁F₃N₄O₃, the formula for (M+H)⁺=485.1567. Found: 485.1577.

Example 19 Methyl(2S)-3-([(1S/R)-1-(4-chlorophenyl)ethyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate

(19a) The free amine (212 mg, 0.61 mmol) derived from the hydrogenationof (S)-1.3 (l=m=0, R³=CO₂Me, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H; cf. procedure (1d) above) was combined with THF (6 mL),glacial acetic acid (0.12 mL), para-chloroacetophenone (142 mg, 0.92mmol), and sodium triacetoxyborohydride (390 mg, 1.83 mmol). Thereaction was stirred for 20 hrs at RT and quenched with sat. NaHCO₃. Theresultant mixture was extracted with EtOAc (1×). The organic extractswere washed with brine, dried (Na₂SO₄), filtered, and concentrated invacuo. The material was purifed by HPLC to give the title ester (1′S/R,2S)-1.5 (l=m=0, R¹=4-chlorophenyl, R¹⁶-methyl, R³=CO₂Me, Z=—C(O)—,R²=3-trifluoromethylphenyl, all other R=H; 54 mg). Exact MS calcd forC₂₂H₂₄Cl₁F₃N₃O₄, the formula for (M+H)⁺=486.1407. Found: 486.1406.

Example 20 Methyl(2S)-3-[[(1S/R)-1-(2,4-dimethylphenyl)ethyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate

(20a) The free amine (323 mg, 0.93 mmol) derived from the hydrogenationof (S)-1.3 (l=m=0, R³=CO₂Me, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H; cf. procedure (1d) above) was dissolved in THF (2.0 mL), andthe resultant solution was charged sequentially with2,4dimethylacetophenone (0.2 mL, 1.35 mmol), powdered 4 Å molecularsieves (202 mg), and glacial acetic acid (0.13 mL). The reaction wasstirred at room temperature for 30 minutes before being treated withsodium triacetoxyborohydride (527 mg, 2.5 mmol). The reaction wasstirred for 30 h at room temperature before being quenched with NaHCO3.The resultant mixture was extracted with EtOAc (2×), and the organicextracts were washed with water (1×), washed with brine (1×), dried(MgSO₄), filtered, and concentrated in vacuo. The material was purifedby HPLC to give the title ester (1′S/R, 2S)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R¹⁶=methyl, R³=CO₂Me, Z=—C(O)—,R²=3-trifluoromethylphenyl, all other R=H; 30 mg). Exact MS calcd forC₂₄H₂₉F₃N₃O₄, the formula for (M+H)⁺=480.2110. Found: 480.2117.

Example 21 Methyl(2S)-3-[(1H-indol-3-ylmethyl)amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate

(21a) Indole-3-carboxaldehyde (43 mg, 0.296 mmol) was incorporated intothe above procedure (1d) to give the title ester (S)-1.5 (l=m=0,R¹=1H-indol-3-yl, R³═CO₂Me, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H; 35 mg). ¹H-NMR (300 MHz, CD₃OD): δ 8.18 (s, 1H), 8.07 (d, 1H,J=7.8 Hz), 7.88 (d, 1H, J=8.1 Hz), 7.74-7.63 (m, 2H), 7.51-7.05 (m, 5H),4.97 (dd, 1H, J=9.2, 4.4 Hz), 4.57 (d, 1H, J=14 Hz), 4.49 (d, 1H, J=14Hz), 4.11 (d, 1H, J=17 Hz), 4.05 (d, 1H, J=17 Hz), 3.76 (s, 3H), 3.64(dd, 1H, J=13, 4.8 Hz), 3.37 (dd, 1H, J=13, 9.1 Hz).

Example 22(2S)-3-[(1H-indol-3-ylmethyl)amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(22a) (S)-1.5 (l=m=0, R¹=1H-indol-3-yl, R³=CO₂Me, Z=—C(O)—,R²=3-trifluoromethylphenyl, all other R=H; 33 mg) was incorporated intothe above procedure (3a) to give (S)-16.2 (R¹=1H-indol-3-yl, Z=—C(O)—,R²=3-trifluoromethylphenyl, all other R=H; 15 mg). MS found:(M+Na)⁺=494.2.

(22b) Ammonia (0.1 mL of a 2.0 M solution) and (S)-16.2(R¹=1H-indol-3-yl, Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H,10.6 mg) were incorporated into the above procedure (4a) to give thetitle amide (S)-16.3 (R¹=1H-indol-3-yl, —C(O)N(R^(3a))₂=—C(O)NH₂,Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H, 0.5 mg). MS found:(M+H)⁺=462.2.

Example 23 Methyl(2S)-3-[(1,3-benzodioxol-5-ylmethyl)amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate

(23a) Piperonal (46 mg, 0.31 mmol) was incorporated into the aboveprocedure (1d) to give the title ester (S)-1.5 (l=m=0,R¹=1,3-benzodioxol-5-yl, R³=CO₂Me, Z=—C(O)—, R²=3-trifluoromethylphenyl,all other R=H; 25 mg). Exact MS calcd for C₂₂H₂₃F₃N₃O₆, the formula for(M+H)⁺=482.1539. Found: 482.1537.

Example 24 Methyl(2S)-3-[[(4-bromophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate

(24a) para-Bromobenzaldehyde (59 mg, 0.32 mmol) was incorporated intothe above procedure (1d) to give the title ester (S)-1.5 (l=m=0,R¹=4-bromophenyl, R³=CO₂Me, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H; 40 mg). Exact MS calcd for C₂₁H₂₂F₃Br₁N₃O₄, the formula for(M+H)⁺=516.0746. Found: 516.0756.

Example 25 Methyl(2S)-2-[[[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanoate

(25a) A solution of the ester (S)-2.2 (l=m=0; 2.25 g, 6.39 mmol; cf.Example 1) in dioxane (32 mL) was treated with 4 N HCl/dioxane (32 mL)and stirred for 12 h at room temperature before being concentrated invacuo. The residue was dissolved in chloroform and concentrated invacuo; this procedure was repeated twice more to give the amine (1.42).MS found: (M+H)⁺=253.3. A solution of the amine (6.3 mmol) in 4:1methylene chloride/DMF (55 mL) was charged with N_(α)-Boc glycine (1.1g, 6.2 mmol), BOP (2.7 g, 6.2 mmol), and N,N-diisopropylethylamine (2.9mL, 17 mmol). The reaction was stirred at RT for 12 hrs and partitionedbetween EtOAc and sat. NaHCO₃. The organic extracts were washed withbrine, dried (Na₂SO₄), filtered, and concentrated in vacuo. The materialwas purifed by flash chromatography to give the desired amide (S)-1.6(l=m=0, R³=CO₂Me, all other R=H, 1.75 g). MS found: (M+Na)⁺=432.1.

(25b) To a solution of the carbamate (S)-1.6 (l=m=0, R³=CO₂Me, all otherR=H, 1.14 g) in methylene chloride (20 mL) was added TFA (5 mL). Thereaction was stirred for 3 h at room temperature and concentrated invacuo. The residue was dissolved in benzene and the solution wasconcentrated in vacuo; this was repeated twice to give the desired amine(806 mg). MS found: (M+H)⁺=310.2.

A solution of the amine (140 mg, 0.46 mmol) in 5:1 methylenechloride/DMF (6 mL) was charged withN-Boc-2-amino-5-(trifluoromethyl)benzoic acid (S. Takagishi, et al.,Synlett 1992, 360; 156 mg, 0.51 mmol), BOP (223 mg, 0.51 mmol), andN,N-diisopropylethylamine (0.2 mL, 1.1 mmol). The reaction was stirredat RT for 12 hrs and partitioned between EtOAc and sat. NaHCO₃. Theorganic extracts were washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The material was purifed by flash chromatographyto give the desired amide (S)-1.3 (1=m=0, PGN=CbzHN, R³=CO₂Me, Z=—C(O)—,R²=N-Boc-2-amino-5-(trifluoromethyl)phenyl, all other R=H; 78 mg). MSfound: (M+Na)⁺=619.2.

(25c) The amide (S)-1.3 (l=m=0, PGN=CbzHN, R³═CO₂Me, Z=—C(O)—,R²=N-Boc-2-amino-5-(trifluoromethyl)phenyl, all other R=H; 78 mg) wasincorporated into the above procedure (1d) to afford the title compound(S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=CO₂Me, Z=—C(O)—,R²=N-Boc-2amino-5-(trifluoromethyl)phenyl, all other R=H; 62 mg). MSFound: (M+H)⁺=581.3.

Example 26 Methyl(2S)-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanoate

(26a) To a solution of the carbamate (S)-1.5 (l=m 0,R¹=2,4-dimethylphenyl, R³=CO₂Me, Z=—C(O)—,R²=N-Boc-2-amino-5-(trifluoromethyl)phenyl, all other R=H; 20 mg) inmethylene chloride (20 mL) was added TFA (5 mL). The reaction wasstirred for 3 h at room temperature and concentrated in vacuo. Theresidue was dissolved in benzene and the solution was concentrated invacuo; this was repeated twice. The residue was purified by reversephase HPLC to give the title compound (S)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R³=CO₂Me, Z=—C(O)—,R²=2-amino-5-(trifluoromethyl)phenyl, all other R=H, 7.1 mg). MS found:(M+H)⁺=481.2.

Example 27(2S)-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(27a) Using an Applied Biosystems 431A peptide synthesizer setup for theFastMOC protocol (piperidine deprotection cycles, HBTU/HOBT/DIEAcoupling cycles, NMP as solvent), Fmoc-PAL resin (PE Biosystems, 0.39mmol/gram; 0.64 g, 0.25 mmol), (S)-N_(α)-Fmoc,N₆₂-Alloc-diaminopropionic acid (0.41 g, 1.0 mmol), N_(α)-Fmoc glycine(0.28 g, 1.0 mmol), and N-Boc-2-amino-5-(trifluoromethyl)benzoic acid(S. Takagishi, et al., Synlett 1992, 360; 0.25, 1.0 mmol) were combinedto provide resin bound (S)-21.6 (l=m=0,R²=N-Boc-2-amino-5-(trifluoromethyl)phenyl, all other R=H; 600 mg).

(27b) The resin (S)-21.6 (l=m=0, R²=2-amino-5-(trifluoromethyl)phenyl,all other R=H, 0.21 g) was loaded into a fritted peptide synthesisvessel and swelled in 37:2:1 CHCl₃/AcOH/N-methyl morpholine (2 mL). Thesuspension was charged with a solution of Pd(PPh₃)₃ (150 mg) in 37:2:1CHCl₃/AcOH/N-methyl morpholine (2 mL), agitated for 2 h at roomtemperature, and then drained in vacuo. The remaining resin was washedconsecutively with 0.5% N,N-diisopropylethylamine/DMF (4 mL), 0.5%sodium diethyldithiocarbamate/DMF (4 mL), methanol (4 mL), methylenechloride (4 mL), methanol (4 mL), and methylene chloride (4 mL) toprovide the resin-bound free amine. This resin tested positive in theninhydrin free amine test. The entirity of the remaining resin wassuspended in 1% AcOH/dimethylacetamide (4 mL); the resulting suspensionwas charged with 2,4-dimethylbenzaldehyde (50 μL) and agitated for 15min. The suspension was treated with sodium cyanoborohydride (ca. 20 mg)and agitated for 12 h at room temperature. The solution was drained invacuo and the resin was resuspended in 1% AcOH/dimethylacetamide (4 mL).The suspension was treated with sodium cyanoborohydride (ca. 20 mg) andagitated for 3 h at room temperature. The solution was drained in vacuoand the resin was washed with methanol (4 mL), methylene chloride (4mL), methanol (4 mL), and methylene chloride (4 mL) to provide theresin-bound benzylamine. The entirity of this resin was suspended in95:5 TFA/H₂O (3 mL), and the resulting suspension was charged withtriethylsilane (50 μL) and agitated for 2 h at room temperature. Thesolution was drained in vacuo, and the resin was washed with TFA (2 mL)and methylene chloride (2×5 mL). The filtrate was concentrated in vacuo.The residue was dissolved in methylene chloride and the resultingsolution was concentrated in vacuo; this procedure was repeated. Theresidue was purified by reverse phase HPLC to afford the title compound(S)-21.8 (l=m=0, R¹=2,4-dimethylphenyl,R²=2-amino-5-(trifluoromethyl)phenyl, all other R=H, 1.3 mg). MS Found:(M+H)⁺=466.3.

Example 28N-[2-[[(1S)-2-[[(2,4-dimethylphenyl)methyl]amino]-1-(hydroxymethyl)ethyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(28a) To a solution of the ester (S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl,R³=CO₂Me, Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H; 15 mg) inmethanol was added sodium borohydride (ca. 3 equivs). The reaction wasstirred for 12 hrs at RT, quenched with sat. NaHCO₃, and extracted withEtOAc (2×). The organic extracts were combined, washed with brine, dried(Na₂SO₄), filtered, and concentrated in vacuo to give the title compound(S)-16.4 (R¹=2,4-dimethylphenyl, Z=—C(O)—, R²=3-trifluoromethylphenyl,all other R=H; 12 mg). MS found: (M+H)⁺=438.3.

Example 29N-[2-[[(1R)-2-[[(2,4-dimethylphenyl)methyl]amino]-1-(hydroxymethyl)ethyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(29a) (R)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³═CO₂Me, Z=—C(O)—,R²=3-trifluoromethylphenyl, all other R=H; 24 mg) was incorporated intothe above procedure (28a) to give the title compound (R)-16.4(R¹=2,4-dimethylphenyl, Z=—C(O)—, R²=3-trifluoromethylphenyl, all otherR=H, 3.2 mg). MS found: (M+H)⁺=438.2.

Example 30N-[2-[[(1S,2S/R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxypropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(30a) To a solution of (S)-N_(α)-Boc, N_(β)-Cbz-diaminopropionic acidDCHA salt (1.13 g, 2.17 mmol) in CH₂Cl₂ (50 mL) was addedN,N-diisopropylethylamine (1.0 mL, 5.4 mmol), N, O-dimethylhydroxylaminehydrochloride (222 mg, 2.3 mmol), and HATU (866 mg, 2.3 mmol). Thereaction was stirred for 12 h at room temperature and partitionedbetween EtOAc and sat. NH₄Cl. The aqueous phase was back-extracted withEtOAc (2×). The organic extracts were combined, washed with sat. NaHCO₃(1×), washed with brine (1×), dried (MgSO₄), filtered, and concentratedin vacuo. The residue was purified via flash chromatography to afford(S)-11.2 (l=m=0, PGN=CbzHN, all other R=H; 840 mg).

(30b) The Weinreb amide (S)-11.2 (l=m=0, PGN=CbzHN, all other R=H; 310mg) was dissolved in THF (8 mL), and the resulting solution was cooledto 0° C. and charged with methyl magnesium bromide (2.2 mL of a 3.0 Msolution). The reaction was stirred at room temperature for 2.5 h beforebeing recooled to 0° C. and quenched with the slow addition of sat.NH₄Cl. The mixture was partitioned between EtOAc and half-sat. NH₄Cl,and the organic phase was washed with brine (1×), dried (MgSO₄),filtered, and concentrated in vacuo to provide the methyl ketone(S)-11.3 (l=m=0, PGN=CbzHN, R=methyl, all other R=H; 248 mg).

(30c) The methyl ketone (S)-11.3 (l=m=0, PGN=CbzHN, R=methyl, all otherR=H; 248 mg) was dissolved in THF (8 mL), and the resultant solution wascharged with EtOH (6 mL), cooled to 0° C., and treated with sodiumborohydride (56 mg). The reaction was stirred at room temperature for 2h and quenched successively with acetone and sat. NH₄Cl. The mixture waspartitioned between EtOAc and half-sat. NH₄Cl, and the organic phase waswashed with brine (1×), dried (MgSO₄), filtered, and concentrated invacuo to provide the alcohol (2S,3S/R)-11.5 (l=m=0, PGN=CbzHN, R=methyl,all other R=H; 227 mg).

(30d) The alcohol (2S,3S/R)-11.5 (l=m=0, PGN=CbzHN, R=methyl, all otherR=H; 227 mg) was incorporated into the procedures (1c) and (1d) toprovide the title compound (1S,2S/R)-1.5 (l=m=0, R¹=2,4-dimethylphenyl,R³=—CH(OH)CH₃, Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H; 5mg). Exact MS calculated for C₂₃H₂₉F₃N₃O₃, the formula for(M+H)+452.2161. Found 452.2167.

Example 31 tert-Butyl(3R)-4-[[(2,4-dimethylphenyl)methyl]amino]-3-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanoate

(31a) To a cooled (0° C.) suspension of D-Boc-Asp(OtBu)-OH (R)-2.4(l=m=0, R³=CH₂CO₂tBu; 2.04 g, 7.05 mmol) in EtOAc (28 mL) was addedN-hydroxysuccinimide (974 mg, 8.5 mmol) and DCC (1.75 g, 8.5 mmol). Thereaction was stirred for 2 h and then filtered. The filtrate was dilutedwith EtOAc and washed with sat. NaHCO₃ (1×) and brine (1×). The organicphase was dried (MgSO₄), filtered, and concentrated in vacuo. Theproduct ester was dissolved in THF (12 mL), and the resultant solutionwas cooled to 0° C. and charged successively with sodium borohydride(293 mg, 7.8 mmol) and ethanol (3.0 mL). The reaction was stirred for 30min at 0° C. and then quenched with sat. NH₄Cl. The mixture wasextracted with EtOAc (2 x), and the organic extracts were dried (MgSO₄),filtered, and concentrated in vacuo to provide the tert-butyl N_(β)Boc(R)-3-amino-4-hydroxybutanoate (1.48 g), which was carried on to (31b)without further purification. A small sample could be purified by flashchromatography for characterization. ¹H-NMR (300 MHz, CD₃OD): δ3.96-3.92 (m, 1H), 3.51 (dd, 1H, J=11, 5.5 Hz), 3.42 (dd, 1H, J=11, 6.2Hz), 2.53 (dd, 1H, J=15, 5.5 Hz), 2.30 (dd, 1H, J=15, 8.4 Hz), 1.45 (s,9H), 1.43 (s, 9H).

(31b) To a cooled (0° C.) solution of the crude tert-butyl N_(β)-Boc(R)-3-amino-4-hydroxybutanoate (1.48 g, 5.38 mmol) in CH₂Cl₂ (75 mL) wasadded 2,6-lutidine (658 μL, 5.7 mmol) and methanesulfonic anhydride(1.25 g, 7.16 mmol). The reaction was stirred for 3 h at roomtemperature before being partitioned between EtOAc and sat. NH₄Cl. Theorganic phase was washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo to give the mesylate (715 mg). A sample could bepurified for characterization by flash chromatography. ¹H-NMR (300 MHz,CDCl₃): δ 5.19 (d, 1H, J=8.4 Hz), 4.30 (d, 2H, J=5.1 Hz), 4.29-4.23 (m,1H), 3.04 (s, 3H), 2.56 (d, 2H, J=5.8 Hz), 1.46 (s, 9H), 1.44 (s, 9H).

(31c) The mesylate (715 mg, 2.03 mmol) was dissolved in DMSO (38 mL),and the resultant solution was charged with sodium azide (660 mg, 10.1mmol) and heated at 65° C. for 14 h. The reaction was filtered, absorbedonto silica gel, and eluted with 80% EtOAc/hexanes to give the azide(R)-2.5 (l=m=0, R=CH₂CO₂LBu; 562 mg). ¹H-NMR (300 MHz, CDCl₃): δ 5.12(bs, 1H), 4.10-4.05 (m, 1H), 3.55-3.39 (m, 2H), 2.49 (d, 5.9 Hz), 1.46(s, 9H), 1.44 (s, 9H).

(31d) The carbamate (R)-2.5 (l=m=0, R³=CH₂CO₂tBu; 562 mg) was chargedwith a solution of anhydrous HCl in EtOAc (prepared from 760 uL of MeOHand 1.33 mL of acetyl chloride in 19 mL of EtOAc), stirred for 12 h atroom temperature, and concentrated in vacuo. The residue was dilutedwith EtOAc and washed with water (1×) and brine (1×). The organic phasewas dried (Na₂SO₄), filtered, and concentrated in vacuo to give theamine (260 mg). This crude product was dissolved in CH₂Cl₂ (12 mL), andthe resultant solution was charged successively with 1.2 (Z=—C(O)—,R²=3-trifluoromethylphenyl; 321 mg, 1.3 mmol), N,N-diisopropylethylamine(453 mL, 2.6 mmol), and BOP (633 mg, 1.4 mmol). The reaction was stirredat room temperature for 14 h and then partitioned between EtOAc and 1NHCl. The organic phase was washed successively with water, sat. NaHCO₃,water, and brine. The organic phase was then dried (MgSO₄), filtered,and concentrated in vacuo to give (R)-1.3 (l=m=0, PGN=N₃, R³=CH₂CO₂tBu,Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H; 493 mg). MSfound: (M+Na)⁺=452.2.

(31e) The azide (R)-1.3 (l=m=0, PGN=N₃, R³=CH₂CO₂tBu, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; 493 mg) was incorporatedinto the above procedure (1d) to give 161 mg of pure product after flashchromatography. A small sample was removed and further purified byRP-HPLC to give the title compound (R)-1.5 (1=m=0,R¹=2,4-dimethylphenyl, R³=CH₂CO₂tBu, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H). Exact MS calcd forC₂₇H₃₅F₃N₃O₄, the formula for (M+H)⁺=522.2580. Found: 522.2575.

Example 32N-[2-[[(1R)-2-[[(2,4-dimethylphenyl)methyl]amino]-1-(phenylmethyl)ethyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(32a) D-N_(α)-Boc phenylalanine (R)-2.4 (l=m=0, R³=CH₂Ph; 2.65 g) wasincorporated into the above procedure (31a), and the product alcohol(1.91 g) was carried on through procedures (31b)-(31e) to give the titlecompound (S)-1.5 (l=m 0, R¹=2,4-dimethylphenyl, R³ CH₂Ph, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; 2 mg). Exact MS calcd forC₂₈H₃₁F₃N₃O₂, the formula for (M+H)⁺=498.2368. Found: 498.2370.

Example 33(2S)-N-tert-Butyl-2-[[[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(33a) A solution of (S)-N_(α)-Boc,N_(β)-Cbz-diaminopropionic acid DCHAsalt (S)-2.1 (l=m=0; 5.01 g, 9.6 mmol) in 90 mL of 8:1 methylenechloride/DMF was treated successively with HATU (3.84 g, 10.1 mmol) andthen tert-butyl amine (3.0 mL, 28.8 mmol). The reaction was stirred atRT for 14 hrs and partitioned between EtOAc and 1 N hydrochloric acid.The organic phase was washed with 5% NaHCO₃ and brine before being dried(MgSO₄), filtered, and concentrated in vacuo. The product was dilutedwith EtOAc, dried again (Na₂SO₄), filtered, and concentrated in vacuo togive the desired amide (S)-2.3 (l=m=0, —C(O)N(R^(3a))₂=—C(O)NHt-Bu; 7.7g). MS found: (M+Na)⁺=416.

(33b) The carbamate (S)-2.3 (l=m=0, —C(O)N(R^(3a))₂—C(O)NHt-Bu; 7.7mmol) was dissolved in 90 mL of 2:1 methylene chloride/TFA and stirredat RT for 3 h before being concentrated in vacuo. The residue wasdissolved in methylene chloride and concentrated in vacuo; thisprocedure was repeated twice more to give the amine (10 g). MS found:(M+H)⁺=294.2. A solution of the amine (estimated as 9.6 mmol) in 6:1methylene chloride/DMF (70 mL) was charged withN,N-diisopropylethylamine (9.0 mL, 48 mmol), N_(α)-Boc glycine (1.86 g,10.6 mmol), and BOP (4.7 g, 10.6 mmol). The reaction was stirred at RTfor 3 days and diluted with EtOAc. The organic extracts were washed withsat. NH₄Cl (2×) and brine (1×), dried (Na₂SO₄), filtered, andconcentrated in vacuo. The material was purifed by flash chromatographyto give the desired amide (S)-1.6 (l=m=0, PGN=CbzHN, R³=CONHt-Bu, allother R=H, 4.5 g). MS found: (M+Na)⁺=473.2.

(33c) To a solution of the carbamate (S)-1.6 (l=m=0, PGN=CbzHN,R³=CONHt-Bu, all other R=H, 0.53 g) in methylene chloride (10 mL) wasadded TFA (4 mL). The reaction was stirred for 3 h at RT andconcentrated in vacuo. The residue was dissolved in methlyene chlorideand the solution was concentrated in vacuo; this was repeated twice. Theresidue was dissolved in benzene and the solution was concentrated invacuo; this was repeated twice. The residue was dissolved in methlyenechloride and the solution was concentrated in vacuo; this was repeatedtwice to give the desired amine. MS found: (M+H)⁺=351.2. A solution ofthe amine (estimated 0.8 mmol) in methylene chloride (6 mL) was chargedsuccessively with N,N-diisopropylethylamine (0.9 mL, 5.2 mmol), asuspension of N-Boc-2-amino-5-(trifluoromethyl)benzoic acid (S.Takagishi, et al., Synlett 1992, 360; 233 mg, 0.76 mmol) in methylenechloride (4 mL; 2 mL DMF rinse), and HATU (320 mg, 0.84 mmol). Thereaction was stirred at RT for 4.5 h and diluted with EtOAc. The organicphase was washed with sat. NH₄Cl (2×), 5% NaHCO₃ (1×), and brine (1×),before being dried (Na₂SO₄), filtered, and concentrated in vacuo to givethe desired amide (S)-1.3 (l=m=0, PGN=CbzHN, R³=CONHL-Bu, Z=—C(O)—,R²=N-Boc-2-amino-5-(trifluoromethyl)phenyl, all other R=H; assumedquantitative). MS found: (M+H)⁺=660.5.

(33d) A solution of the amide (S)-1.3 (l=m=0, PGN=CbzHN, R³=CONHt-Bu,Z=—C(O)—, R²=N-Boc-2-amino-5-(trifluoromethyl)phenyl, all other R=H;assumed 0.8 mmol) in MeOH (10 mL) was charged with 5% Pd/C, Degussa (100mg). The reaction vessel was purged with hydrogen gas (2×) and stirredunder hydrogen (1 atm) for 10 h before being filtered and concentratedin vacuo to give the amine (S)-1.4 (l=m=0, R³=CONHt-Bu, Z=—C(O)—,R²=N-Boc-2-amino-5-(trifluoromethyl)phenyl, all other R=H; assumed 0.8mmol) as a light yellow oil. MS found: (M+H)⁺=504.4

(33e) A solution of the amine (S)-1.4 (l=m=0, R³=CONHt-Bu, Z=—C(O)—,R²=N-Boc-2-amino-5-(trifluoromethyl)phenyl, all other R=H; assumed 0.35mmol) in MeOH (4 mL) was charged with 2,4-dimethylbenzaldehyde (0.05 mL,0.35 mmol) and stirred for 8 min at RT before being charged with sodiumcyanoborohydride (44 mg, 0.70 mmol) and stirred for 4 h at RT. Thereaction was quenched with the addition of sat. NaHCO₃ and thenextracted with EtOAc (2×). The organic extracts were combined, washedwith brine, dried (MgSO₄), filtered, and concentrated in vacuo. Thecrude product was purified by reverse-phase HPLC to afford the titlecompound (S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=CONHt-Bu, Z=—C(O)—,R²=N-Boc-2-amino-5-(trifluoromethyl)phenyl, all other R=H; 12 mg) as awhite powder after lyopholization. Exact MS calcd for C₃₁H₄₃F₃N₅O₅, theformula for (M+H)⁺=622.3216. Found: 622.3219.

Example 34(2S)-N-tert-Butyl-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(34a) A solution of (S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=CONHt-Bu,Z=—C(O)—, R²=N-Boc-2-amino-5-(trifluoromethyl)phenyl, all other R=H; 5mg) in methylene chloride (8 mL) was charged with TFA (4 mL) and stirredat RT for 3 h before being concentrated in vacuo. The residue wasdissolved in methylene chloride and the solution was concentrated invacuo. The crude product was purified by reverse-phase HPLC to affordthe title compound (S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=CONHt-Bu,Z=—C(O)—, R²=2-amino-5-(trifluoromethyl)phenyl, all other R=H; 5 mg) asa white powder after lyopholization. Exact MS calcd for C₂₆H₃₅F₃N₅O₃,the formula for (M+H)⁺=522.2692. Found: 522.2707.

Example 35 (2S)-N-tert-Butyl-3-[[(4-bromo,2-methylphenyl)methyl]amino]-2-[[[[2-[[(1,1dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(35a) 4-Bromo, 2-methylbenzaldehyde (M. I. Dawson, et al., J. Med. Chem.1984, 27, 1516-1531; 0.05 mL) was incorporated into the above procedure(33e) to provide the title compound (S)-1.5 (l=m=0,R¹=4-bromo,2-methylphenyl, R³=CONHt-Bu, Z=—C(O)—,R²=N-Boc-2-amino-5-(trifluoromethyl)phenyl, all other R=H; 11 mg) as awhite powder after lyopholization. Exact MS calcd for C₃₀H₄₀Br₁F₃N₅O₅,the formula for (M+H)⁺=686.2165. Found: 686.2173.

Example 36(2S)-N-tert-Butyl-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(4-bromo,2-methylphenyl)methyl]amino]-propanamide

(36a) The compound (S)-1.5 (l=m=0, R¹=4-bromo,2-methylphenyl,R³=CONHt-Bu, Z=—C(O)—, R²=N-Boc-2-amino-5-(trifluoromethyl)phenyl, allother R=H; 5 mg) was incorporated into the above procedure (35a) toafford the title compound (S)-1.5 (l=m=0, R¹=4-bromo,2-methylphenyl,R³=CONHt-Bu, Z=—C(O)—, R²=2-amino-5-(trifluoromethyl)phenyl, all otherR=H; 3 mg) as a white powder after lyopholization. Exact MS calcd forC₃₀H₄₀Br₁F₃N₅O₅, the formula for (M+H)⁺=586.1641. Found: 586.1635.

Example 37N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-3(methyl)butyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(37a) The Weinreb amide (S)-11.2 (l=m=0, PGN=CbzHN, all other R=H; cf.procedure (30a); 365 mg, 0.96 mmol) and iso-propylmagnesium bromide (2.9mL of a 2.0 M solution in THF) were incorporated into the aboveprocedure (30b). The resultant product was carried through procedure(30c) to provide (2S,3S/R)-11.5 (l=m=0, PGN=CbzHN, R=iso-propyl, allother R=H; assumed 0.96 mmol). MS found: (M+Na)⁺=389.1.

(37b) The alcohol (2S,3S/R)-11.5 (l=m=0, PGN=CbzHN, R=iso-propyl, allother R=H; assumed 0.96 mmol) was incorporated into the procedures (1c)and (1d) to provide (1S,2S/R)-1.5 (l=m=0, R¹=2,4-dimethylphenyl,R³=—CH(OH)i-Pr, Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H;120 mg). MS found: (M+H)⁺=480.5.

(37c) To a solution of the amine (1S,2S/R)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R³=—CH(OH)i-Pr, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; ca. 0.4 mmol) in 4 mL of1:1 THF/H₂O was added triethylamine (0.07 mL, 0.5 mmol) anddi-tert-butyldicarbonate (110 mg, 0.5 mmol). The reaction was stirredfor 3 days at RT and then partitioned between EtOAc and sat. NaHCO₃. Theorganic phase was washed with sat. NaCl, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude product was purified by flashchromatography in order to separate the two diastereomers, which weredeprotected independently as described below in procedures (37d) and(38a).

(37d) The minor diastereomer from procedure (37c) was dissolved inmethylene chloride (4 mL) and treated with TFA (2 mL). The reaction wasstirred for 3 h at RT before being concentrated in vacuo. The residuewas dissolved in methylene chloride and the solution was concentrated invacuo; this procedure was repeated once more. The crude product thusobtained was purified by RP-HPLC to afford the title compound(1S,2S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=—CH(OH)i-Pr,Z=—C(O)—R²=3-(trifluoromethyl)phenyl, all other R=H; 120 mg) as a whitepowder after lyopholization. MS found: (M+H)⁺=480.5.

Example 38N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-3-(methyl)butyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(38a) The major diastereomer obtained from procedure (37c) was processedaccording to procedure (37d). The crude product thus obtained waspurified by RP-HPLC to afford the title compound (1S,2R)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R³=—CH(OH)i-Pr, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; 120 mg) as a white powderafter lyopholization. MS found: (M+H)⁺=480.5.

Example 39N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(phenyl)ethyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(39a) The Weinreb amide (S)-11.2 (l=m=0, PGN=CbzHN, all other R=H; cf.procedure (30a); 403 mg, 1.06 mmol) and phenylmagnesium bromide (6.4 mLof a 1.0 M solution in THF) were incorporated into the above procedure(30b). The resultant product was carried through procedure (30c) toprovide (2S,3S/R)-11.5 (l=m=0, PGN=CbzHN, R=phenyl, all other R=H;assumed 1.06 mmol). MS found: (M+Na)⁺=421.1.

(39b) The alcohol (2S,3S/R)-11.5 (l=m=0, PGN=CbzHN, R=phenyl, all otherR=H; assumed 1.06 mmol) was incorporated into the procedures (1c) and(1d) to provide (1S,2S/R)-1.5 (l=m=0, R¹=2,4-dimethylphenyl,R³=—CH(OH)Ph, Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H; 63mg) as a white powder after lyopholization. MS found: (M+H)⁺=514.2.

(39c) The diastereomeric mixture of alcohols (1S,2S/R)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R³=—CH(OH)Ph, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H) was purified further byHPLC with a chiral column (Chiracel OD) in order to separate the twodiastereomers. The second peak to elute from the column (minordiastereomer) was the title compound (1S,2S)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R³=—CH(OH)Ph, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H).

Example 40N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(phenyl)ethyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(40a) The diastereomeric mixture of alcohols (1S,2S/R)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R³=—CH(OH)Ph, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H) obtained from procedure(39b) was purified further by HPLC with a chiral column (Chiracel OD) inorder to separate the two diastereomers. The first peak to elute fromthe column (major diastereomer) was the title compound (1S,2R)-1.5(l=m=0, R¹=2,4-dimethylphenyl, R³=—CH(OH)Ph, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H).

Example 41N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-3-(phenyl)propyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(41a) The Weinreb amide (S)-11.2 (l=m=0, PGN=CbzHN, all other R=H; cf.procedure (30a); 311 mg, 0.82 mmol) and benzylmagnesium bromide (2.5 mLof a 2.0 M solution in THF) were incorporated into the above procedure(30b). The resultant product was carried through procedure (30c) toprovide (2S,3S/R)-11.5 (l=m=0, PGN=CbzHN, R=benzyl, all other R=H;assumed 0.82 mmol).

(41b) The alcohol (2S,3S/R)-11.5 (l=m=0, PGN=CbzHN, R=phenyl, all otherR=H; assumed 0.82 mmol) was incorporated into the procedures (1c) and(1d) to provide (1S,2S/R)-1.5 (l=m=0, R¹=2,4-dimethylphenyl,R³=—CH(OH)CH₂Ph, Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H;40 mg) as a white powder after RP-HPLC and lyopholization. MS found:(M+H)⁺=528.2.

(41c) The unpurified mixture of diastereomers (1S,2S/R)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R³=—CH(OH)CH₂Ph, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; assumed 0.4 mmol) wasincorporated into the above procedure (37c). The crude product waspurified by flash chromatography in order to separate the twodiastereomers, which were deprotected independently as described belowin procedures (41d) and (42a).

(41d) The minor product from procedure (41c) was incorporated intoprocedure (37d) to provide the title compound (1S,2S)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R³=—CH(OH)CH₂Ph, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; 10 mg) as a white powderafter RP-HPLC and lyopholization. MS found: (M+H)⁺=528.5.

Example 42N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-3-(phenyl)propyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(42a) The major product from procedure (41c) was incorporated intoprocedure (37d) to provide the title compound (1S,2R)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R³=—CH(OH)CH₂Ph, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; 10 mg) as a white powderafter RP-HPLC and lyopholization. MS found: (M+H)⁺=528.5.

Example 43N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-4-(methyl)pentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(43a) The Weinreb amide (S)-11.2 (l=m=0, PGN=CbzHN, all other R=H; cf.procedure (30a); 540 mg, 1.42 mmol) and isobutylmagnesium bromide (4.3mL of a 2.0 M solution in Et₂O) were incorporated into the aboveprocedure (30b). The resultant product was carried through procedure(30c) to provide (2S,3S/R)-11.5 (l=m=0, PGN=CbzHN, R=iso-butyl, allother R=H; assumed 1.4 mmol). MS found: (M+Na)⁺=403.3.

(43b) The alcohol (2S,3S/R)-11.5 (l=m=0, PGN=CbzHN, R=iso-butyl, allother R=H; assumed 1.4 mmol) was incorporated into the procedures (1c)and (1d) to provide (1S,2S/R)-1.5 (l=m=0, R¹=2,4-dimethylphenyl,R³=—CH(OH)CH₂i-Pr, Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all otherR=H; 33 mg) as a white powder after RP-HPLC and lyopholization. MSfound: (M+H)⁺=480.5.

(43c) The unpurified mixture of diastereomers (1S,2S/R)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R³=—CH(OH)CH₂i-Pr, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; assumed 0.4 mmol) wasincorporated into the above procedure (37c). The crude product waspurified by flash chromatography in order to separate the twodiastereomers, which were deprotected independently as described belowin procedures (43d) and (44a).

(43d) The minor product from procedure (43c) was incorporated intoprocedure (37d) to provide the title compound (1S,2S)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R³=—CH(OH)CH₂i-Pr, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; 10 mg) as a white powderafter RP-HPLC and lyopholization. MS found: (M+H)⁺=480.5.

Example 44N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-4-(methyl)pentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(44a) The major product from procedure (43c) was incorporated intoprocedure (37d) to provide the title compound (1S,2R)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R³=—CH(OH)CH₂i-Pr, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; 10 mg) as a white powderafter RP-HPLC and lyopholization. MS found: (M+H)⁺=480.5.

Example 45N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)butyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(45a) The Weinreb amide (S)-11.2 (l=m=0, PGN=CbzHN, all other R=H; cf.procedure (30a); 530 mg, 1.39 mmol) and ethylmagnesium bromide (4.2 mLof a 2.0 M solution in THF) were incorporated into the above procedure(30b). The resultant product was carried through procedure (30c) toprovide (2S,3S/R)-11.5 (l=m=0, PGN=CbzHN, R=ethyl, all other R=H;assumed 1.4 mmol). MS found: (M+Na)⁺=375.2.

(45b) The mixture of diastereomers (2S,3S/R)-11.5 (l=m=0, PGN=CbzHN,R=ethyl, all other R=H; assumed 1.4 mmol) was dissolved in 2:1acetone/dimethoxypropane (15 mL) and the resultant solution was chargedwith a pinch of camphorsulfonic acid. The reaction was stirred for 14 hat RT, quenched with 0.2 mL of triethylamine, and concentrated in vacuo.The residue was purified by flash chromatography to provide theN,O-acetal (274 mg). MS found: (M+Na)⁺=415.1.

(45c) The N,O-acetal (274 mg, 0.68 mmol) was incorporated into procedure(1d) to provide the benzyl amine. MS found: (M+H)⁺=377.5. This materialwas not purified, but rather dissolved in 10 mL of 1:1 THF/H₂O. Thesolution was charged with triethylamine (0.19 mL, 1.36 mmol) and thentreated with dibenzyldicarbonate (234 mg, 0.82 mmol). The reaction wasstirred for 3 days at RT and then partitioned between EtOAc and sat.NH₄Cl. The organic phase was washed with brine, dried (MgSO₄), filtered,and concentrated in vacuo. The residue was purified by flashchromatography in order to separate the two diastereomers. The MS foundfor each diastereomer was identical: (M+Na)⁺=533.2.

(45d) The faster-eluting diastereomer (minor product, 47 mg, 0.09 mmol)obtained from procedure (45c) was dissolved in THF (2 mL), H₂O (1 mL),and glacial acetic acid (4 mL). The solution was stirred for 96 h at RTand then partitioned between EtOAc and sat. NaHCO₃. The organic phasewas washed with 5% NaHCO₃ (1×) and brine (1×) before being dried(Na₂SO₄), filtered, and concentrated in vacuo to provide (2S,3S)-11.5(l=m=0, PGN=2,4-Me₂PhCH₂-(Cbz)N, R=ethyl, all other R=H; assumed 0.09mmol). MS found: (M+H)⁺=471.3.

(45e) The compound (2S,3S)-11.5 (l=m=0, PGN=2,4-Me₂PhCH₂-(Cbz)N,R=ethyl, all other R=H; assumed 0.9 mmol) was incorporated into theabove procedure (1c) to afford (1S,2S)-1.4 (l=m=0,PGN=2,4-Me₂PhCH₂(Cbz)N, R³=—CH(OH)Et, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; assumed 0.09 mmol) as acrude product. MS found: (M+Na)⁺=622.2. This material was dissolved inMeOH (3 mL) and the solution was charged with 5% Pd/C, Degussa (12 mg).The reaction vessel was purged with hydrogen, and the reaction wasstirred under hydrogen (1 atm) for 14 h at RT. The reaction was filteredand concentrated in vacuo. The residue was purified by RP-HPLC to affordthe title compound (1S,2S)-1.5 (l=m=0, R¹=2,4dimethylphenyl,R³=—CH(OH)Et, Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H; 10mg) as a white powder after lyopholization. Exact MS calcd forC₂₄H₃₁F₃N₃O₃, the formula for (M+H)⁺=466.2318. Found: 466.2342.

Example 46N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)butyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(46a) The faster-eluting diastereomer (major product, 85 mg, 0.22 mmol)obtained from procedure (45c) was incorporated into procedures (45d) and(45e). The resultant residue was purified by RP-HPLC to afford the titlecompound (1S,2R)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=—CH(OH)Et,Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H; 20 mg) as a whitepowder after lyopholization. Exact MS calcd for C₂₄H₃₁F₃N₃O₃, theformula for (M+H)⁺=466.2318. Found: 466.2317.

Example 47N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)butyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide

(47a) A solution of H-Gly-OBn (p-Tos salt; 6.0 g, 17.9 mmol) in DMF (45mL) was charged successively with N,N-diisopropylethylamine (12.4 mL,71.5 mmol), N-Boc-2-amino-5-(trifluoromethyl)benzoic acid (S. Takagishi,et al., Synlett 1992, 360; 6.0 g, 19.7 mmol), and BOP (8.69 g, 19.7mmol). The reaction was stirred at RT for 3 days, diluted with EtOAc,and washed with brine (pH 5, 1 x), H₂O (1×), sat. NaHCO₃ (1×), and brine(1×). The organic phase was dried (MgSO₄), filtered, and concentrated invacuo. The residue was purified by flash chromatography to provide theamide (5.78 g, 12.8 mmol). MS found: (M+Na)⁺=475.3. This material wasdissolved in MeOH (50 mL) and the solution was charged with 10% Pd/C,Degussa (1.0 g). The vessel was purged with hydrogen, and the reactionwas stirred under hydrogen (1 atm) for 3 h before being filtered. Thefiltrate was concentrated in vacuo to afford 1.2 (Z=—C(O)—, R²=N-Boc2-amino-5-(trifluoromethyl)benzoic acid, all other R=H, 4.56 g) as awhite solid. MS found: (M−H)-=361.3.

(47b) Both 1.2 (Z=—C(O)—, R²=N-Boc 2-amino-5-(trifluoromethyl)benzoicacid, all other R=H; 73 mg, 0.2 mmol) and the compound (2S,3S)-11.5(l=m=0, PGN=2,4-Me₂PhCH₂(Cbz)N, R=ethyl, all other R=H; cf. procedure(45d); 86 mg, 0.18 mmol) were incorporated into the above procedure (1c)to afford (1S,2S)-1.4 (l=m=0, PGN=2,4-Me₂PhCH₂(Cbz)N, R³=—CH(OH)Et,Z=—C(O)—, R²=N-Boc 2-amino-5-(trifluoromethyl)phenyl, all other R=H;assumed 0.18 mmol) after flash chromatography. This material wasdissolved in MeOH (5 mL) and the solution was charged with 5% Pd/C,Degussa (20 mg). The reaction vessel was purged with hydrogen, and thereaction was stirred under hydrogen (1 atm) for 45 min at RT. Thereaction was filtered and concentrated in vacuo to afford the titlecompound (1S,2S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=—CH(OH)Et,Z=—C(O)—, R²=N-Boc 2-amino-5-(trifluoromethyl)phenyl, all other R=H; 80mg). MS found: (M+H)⁺=581.4.

Example 48N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)butyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide

(48a) The compound (1S,2S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl,R³=—CH(OH)Et, Z=—C(O)—, R²=N-Boc 2-amino-5-(trifluoromethyl)phenyl, allother R=H; 75 mg) was dissolved in 6 mL of 2:1 methylene chloride/TFAand stirred at RT for 80 min before being concentrated in vacuo. Theresidue was purified by RP-HPLC to afford the title compound (1S,2S)-1.5(l=m=0, R¹=2,4-dimethylphenyl, R³=—CH(OH)Et, Z=—C(O)—,R²=2-amino-5-(trifluoromethyl)phenyl, all other R=H; 60 mg) as a whitepowder after lyopholization. Exact MS calcd for C₂₄H₃₂F₃N₄O₃, theformula for (M+H)⁺=481.2426. Found: 481.2407.

Example 49N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-4-(methyl)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide

(49a) The crude product mixture from procedure (43a) was purified byflash chromatography to provide separation of the two diastereomers(2S,3S)— and (2S,3R)-11.5 (l=m=0, PGN=CbzHN, R=iso-butyl, all otherR=H). The minor, faster-eluting (2S,3S)-isomer (95 mg, 0.25 mmol), wascombined with 1.2 (Z=—C(O)—, R²=N-Boc 2-amino-5-(trifluoromethyl)benzoicacid, all other R=H; cf. procedure (47a); 94 mg, 0.26 mmol) in procedure(1c). The product from this reaction was then taken through procedure(1d). RP-HPLC afforded the title compound (1S, 2S)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R³=—CH(OH)i-Bu, Z=—C(O)—, R²=N-Boc2-amino-5-(trifluoromethyl)phenyl, all other R=H; 10 mg) as a whitepowder after lyopholization. Exact MS calcd for C₃₁H₄₄F₃N₄O₅, theformula for (M+H)⁺=609.3264. Found: 609.3267.

Example 50N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-4-(methyl)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide

(50a) The major, slower-eluting (2S,3R)-isomer (86 mg, 0.35 mmol) fromprocedure (49a) was taken through procedure (1d). The product wascombined with 1.2 (Z=—C(O)—, R²=N-Boc 2-amino-5-(trifluoromethyl)benzoicacid, all other R=H; cf. procedure (47a); 31 mg, 0.09 mmol) in procedure(1c). RP-HPLC afforded the title compound (1S,2R)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R³=—CH(OH)i-Bu, Z=—C(O)—, R²=N-Boc2-amino-5-(trifluoromethyl)phenyl, all other R=H; 5 mg) as a whitepowder after lyopholization. Exact MS calcd for C₃₁H₄₄F₃N₄O₅, theformula for (M+H)⁺=609.3264. Found: 609.3250.

Example 51N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-4-(methyl)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide

(51a) The product from procedure (49a) was taken through procedure (48a)and then purified by RP-HPLC to afford the title compound (1S,2S)-1.5(l=m=0, R¹=2,4-dimethylphenyl, R³=—CH(OH)i-Bu, Z=—C(O)—,R²=2-amino-5-(trifluoromethyl)phenyl, all other R=H; 3 mg). MS found:(M+H)⁺=509.3.

Example 52N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-4-(methyl)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide

(52a) The product from procedure (50a) was taken through procedure (48a)and then purified by RP-HPLC to afford the title compound (1S,2R)-1.5(l=m=0, R¹=2,4-dimethylphenyl, R³=—CH(OH)i-Bu, Z=—C(O)—,R²=2-amino-5-(trifluoromethyl)phenyl, all other R=H; 10 mg) as a whitepowder after lyopholization. MS found: (M+H)⁺=509.5.

Example 53N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-4,4-dimethyl-2-(hydroxy)pentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(53a) The Weinreb amide (S)-11.2 (l=m=0, PGN=CbzHN, all other R=H; cf.procedure (30a); 850 mg, 2.23 mmol) and neopentylmagnesium bromide (13.4mL of a 1.0 M solution in THF) were incorporated into the aboveprocedure (30b). The resultant product was carried through procedure(30c). The crude mixture of diastereomeric alcohols were separated byflash chromatography to provide (2S,3S)-11.5 (l=m=0, PGN=CbzHN,R═CH₂t-Bu, all other R=H; 31 mg) and (2S,3R)-11.5 (l=m=0, PGN=CbzHN,R═CH₂t-Bu, all other R=H; 199 mg).

(53b) The (2S,3S)-diastereomer from (53a) was carried through procedures(1c) and (1d). The crude product was purified by RP-HPLC to afford thetitle compound (1S, 2S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl,R³=—CH(OH)CH₂t-Bu, Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all otherR=H; 5 mg) as a white powder after lyopholization. Exact MS calcd forC₂₇H₃₇F₃N₃O₃, the formula for (M+H)⁺=508.2787. Found: 508.2778.

Example 54N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-4,4-dimethyl-2-(hydroxy)pentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(54a) The (2S,3R)-diastereomer from (53a) was carried through procedures(1c) and (1d). The crude product was purified by RP-HPLC to afford thetitle compound (1S, 2S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl,R³=—CH(OH)CH₂t-Bu, Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all otherR=H; 10 mg) as a white powder after lyopholization. Exact MS calcd forC₂₇H₃₇F₃N₃O₃, the formula for (M+H)⁺=508.2787. Found: 508.2774.

Example 55N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(55a) The Weinreb amide (S)-11.2 (l=m=0, PGN=CbzHN, all other R=H; cf.procedure (30a); 894 mg, 2.34 mmol) and propylmagnesium bromide (7.0 mLof a 2.0 M solution in Et₂O) were incorporated into the above procedure(30b). The resultant product was carried through procedure (30c). Thecrude mixture of diastereomeric alcohols was then carried throughprocedure (1d). The product (632 mg) was dissolved in THF (27 mL) andthe solution was charged with triethylamine (0.72 mL, 5.41 mmol) anddibenzyldicarbonate (618 mg, 2.16 mmol). The reaction was stirred for 14h, concentrated in vacuo, dissolved in EtOAc, and washed with 1N HCl(1×), H₂O (1×), and brine (1×). The organic extract was dried (Na₂SO₄),filtered, and concentrated in vacuo to afford the mixture ofdiastereomers as an oil (188 mg). The mixture was separated by repeatedflash chromatography (SiO₂) to provide pure fractions of (2S,3S)- and(2S, 3R)-11.5 (l=m=0, PGN=2,4-Me₂Bn(Cbz)N, R=propyl, all other R=H), aswell as fractions that contained both diastereomers.

(55b) The (2S,3S)-diastereomer (29 mg, 0.074 mmol) from (55a) wascarried through procedure (1c). The crude product (43 mg) was dissolvedin MeOH (2 mL) and the solution was charged with 5% Pd/C, Degussa (9mg). The vessel was purged with hydrogen and the reaction was stirredunder hydrogen (1 atm) for 14 h before it was filtered and concentratedin vacuo. The residue was purified by RP-HPLC to afford the titlecompound (1S, 2S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl,R³=—CH(OH)_(n)-propyl, Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all otherR=H; 5 mg) as a white powder after lyopholization. Exact MS calcd forC₂₅H₃₃F₃N₃O₃, the formula for (M+H)⁺=480.2474. Found: 480.2480.

Example 56N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(56a) The (2S,3R)-diastereomer (30 mg, 0.078 mmol) from (55a) wascarried through procedure (1c). The crude product was dissolved in MeOH(3 mL) and the solution was charged with 5% Pd/C, Degussa (10 mg). Thevessel was purged with hydrogen and the reaction was stirred underhydrogen (1 atm) for 14 h before it was filtered and concentrated invacuo. The residue was purified by RP-HPLC to afford the title compound(1S,2R)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=—CH(OH)n-propyl, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; 8 mg) as a white powderafter lyopholization. Exact MS calcd for C₂₅H₃₃F₃N₃O₃, the formula for(M+H)⁺=480.2474. Found: 480.2478.

Example 57N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide

(57a) An purified, but incompletely separated mixture of diastereomers(128 mg, 0.33 mmol) from procedure (55a) was combined with 1.2(Z=—C(O)—, R²=N-Boc 2-amino-5-(trifluoromethyl)benzoic acid, all otherR=H; cf. procedure (47a); 87 mg, 0.33 mmol) in procedure (1c). Theresidue thus obtained was purified by flash chromatography to separatethe alcohol diastereomers.

(57b) The minor diastereomer (25 mg, 0.03 mmol) from (57a) was dissolvedin in MeOH (2 mL) and the solution was charged with 5% Pd/C, Degussa (5mg). The vessel was purged with hydrogen and the reaction was stirredunder hydrogen (1 atm) for 14 h before it was filtered and concentratedin vacuo. The residue was purified by RP-HPLC to afford the titlecompound (1S,2S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=—CH(OH)n-propyl,Z=—C(O)—, R²=N-Boc 2-amino-5-(trifluoromethyl)phenyl, all other R=H; 7mg). MS found: (M+H)⁺=595.5.

Example 58N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide

(58a) The major diastereomer (75 mg, 0.10 mmol) from (57a) was dissolvedin in MeOH (3 mL) and the solution was charged with 5% Pd/C, Degussa (15mg). The vessel was purged with hydrogen and the reaction was stirredunder hydrogen (1 atm) for 14 h before it was filtered and concentratedin vacuo. The residue was purified by RP-HPLC to afford the titlecompound (1S,2R)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=—CH(OH)n-propyl,Z=—C(O)—, R²=N-Boc 2-amino-5-(trifluoromethyl)phenyl, all other R=H; 20mg). Exact MS calcd for C₃₀H₄₂F₃N₄O₅, the formula for (M+H)⁺=595.3107.Found: 595.3110.

Example 59N-(2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide

(59a) The product (5 mg) from procedure (57b) was carried throughprocedure (48a) to afford the title compound (1S, 2S)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R³=—CH(OH)n-propyl, Z=—C(O)—,R²=2-amino-5-(trifluoromethyl)phenyl, all other R=H; 1 mg) after RP-HPLCand lyopholization. MS found: (M+H)⁺=495.4.

Example 60N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide

(60a) The product (15 mg) from procedure (58a) was carried throughprocedure (48a) to afford the title compound (1S,2R)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R³=—CH(OH)n-propyl, Z=—C(O)—,R²=2-amino-5-(trifluoromethyl)phenyl, all other R=H; 3 mg) after RP-HPLCand lyopholization. Exact MS calcd for C₂₅H₃₄F₃N₄O₃, the formula for(M+H)⁺=495.2583. Found: 495.2584.

Example 61N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-3-amino-5-(trifluoromethyl)benzamide

(61a) A solution of 3-nitro-5(trifluoromethyl)benzoic acid (7.71 g, 32.8mmol) and glycine tert-butyl ester (5.23 g, 32.4 mmol) in methylenechloride (330 mL) was charged with N,N-diisopropylethylamine (5.5 mL,31.8 mmol) and BOP (14.6 g, 32.9 mmol). The reaction was stirred at RTfor 14 h, concentrated in vacuo, and diluted with EtOAc (1 L). Theorganic phase was washed successively with sat. NH₄Cl, sat. NaHCO₃, andbrine before being dried (Na₂SO₄), filtered, and concentrated in vacuo.The residue was purified by flash chromatography (SiO₂, 50%EtOAc/hexanes) to afford the tert-Butyl.(3-trifluoromethylbenzoyl)glycine as an oil. A portion (1.0 g, 2.65mmol) of this material was dissolved in methylene chloride (8 mL) beforebeing treated with TFA (4 mL). The reaction was stirred for 1 h at RTand then concentrated in vacuo. The residue was dissolved in methlyenechloride and concentrated again; this procedure was repeated twice moreto afford the title compound 1.2 (Z=—C(O)—,R²=3-amino-5-(trifluoromethyl)phenyl, all other R=H, 0.77 g) as a whitesolid. MS found: (M−H)=291.1.

(61b) A cooled (0° C.) solution of the Weinreb amide (S)-11.2 (l=m=0,PGN=CbzHN, all other R=H, 7.7 g, 20 mmol) in THF (100 mL) was treatedwith propylmagnesium bromide (50 mL of a 2.0 M solution in THF). Thereaction was allowed to warm to RT over 2 h and then recooled to 0° C.before being quenched with the addition of sat. NH₄Cl. The mixture wasdiluted with H₂O and extracted with EtOAc (2×). The organic phase waswashed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuo.The resultant ketone was dissolved in THF (70 mL) and EtOH (30 mL). Thesolution was cooled to 0° C., charged with sodium borohydride (1.5 g, 40mmol), and then stirred at RT for 3 h before being quenched with sat.NaHCO₃. The mixture was extracted with EtOAc (2×), and the organic phasewas washed with brine, dried (Na₂SO₄), filtered, and concentrated invacuo. The residue was purified by repeated flash chromatography (SiO₂)to provide (2S,3S)— and (2S,3R)-11.5 (l=m=0, PGN=CbzHN, R=propyl, allother R=H) in a circa 1:10 ratio. MS found: (M+Na)⁺=389.4.

(61c) The minor, (2S,3S)-diastereomer (84 mg, 0.22 mmol) from (61b) and1.2 (Z=—C(O)—, R²=3-amino-5-(trifluoromethyl)phenyl, all other R=H; 64mg, 0.22 mmol) were combined in procedure (1c). The resultant productwas taken through procedure (1d) and then purified by RP-HPLC to affordthe title compound (1S, 2S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl,R³=—CH(OH)_(n)-propyl, Z=—C(O)—, R²=3-amino-5-(trifluoromethyl)phenyl,all other R=H; 15 mg). Exact MS calcd for C₂₅H₃₄F₃N₄O₃, the formula for(M+H)⁺=495.2583. Found: 495.2584.

Example 62N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-3-amino-5-(trifluoromethyl)benzamide

(62a) The major, (2S,3R)-diastereomer (194 mg, 0.73 mmol) from (61b) and1.2 (Z=—C(O)—, R²=3-amino-5-(trifluoromethyl)phenyl, all other R=H; cf.procedure (61a); 218 mg, 0.61 mmol) were combined in procedure (1c). Theresultant product was taken through procedure (1d) and then purified byRP-HPLC to afford the title compound (1S,2S)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R³=—CH(OH)n-propyl, Z=—C(O)—,R²=3-amino-5-(trifluoromethyl)phenyl, all other R=H; 15 mg). Exact MScalcd for C₂₅H₃₄F₃N₄O₃, the formula for (M+H)⁺=495.2583. Found:495.2586.

Example 63N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(ethylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide

(63a) N-Boc 2-amino-5-(trifluoromethyl)benzoic acid (S. Takagishi, etal., Synlett 1992, 360; 5.1 g, 17 mmol) was dissolved in DMF (42 mL) andthe solution was charged with allyl bromide (3.8 mL, 44 mmol) andpotassium carbonate (3.4 g, 25 mmol). The slurry was stirred for 14 h atRT, diluted with EtOAc, and washed successively with brine, water, andbrine. The organic phase was dried (Na₂SO₄), filtered, and concentratedin vacuo to provide the allyl ester as a white solid. This material wasdissolved in methylene chloride (30 mL) and TFA (15 mL) and stirred atRT for 2 h before being concentrated in vacuo. The residue was dissolvedin methylene chloride and the solution was concentrated in vacuo; thisprocedure was repeated twice. The residue was purified by flashchromatography (SiO₂) to provide the amine as an oil (contaminated withsome DMF). The amine (ca. 15.7 mmol) was dissolved in THF (30 mL) andadded dropwise to a solution of disphosgene (5.6 mL, 47 mmol) in THF (30mL). The reaction was stirred for 14 h at RT and concentrated in vacuoto afford a brown solid. A portion (2.4 g, ca. 7.7 mmol) of the brownsolid was dissolved in THF (40 mL) and the solution was charged withethylamine (20 mL of a 2.0 M solution in THF). The reaction was stirredfor 14 h at RT and then diluted with EtOAc. The organic phase was washedsuccessively with 1N HCl (2×) and brine (1×) before being dried(Na₂SO₄), filtered, and concentrated in vacuo to give a white solid.This material (1.8 g, ca. 5.7 mmol) was dissolved in acetonitrile (25mL) and DMF (20 mL). The solution was charged with pyrolidine (1.0 mL,12 mmol) and Ph(PPh₃)₄ (140 mg, 0.17 mmol) and then stirred for 2 h atRT before being concentrated in vacuo. The residue was diluted withEtOAc and this was washed successively with 1N HCl (2×) and brine (1×)before being dried (Na₂SO₄), filtered, and concentrated in vacuo. Theresidue was triturated with methylene chloride to afford pure2-[[(ethylamino)carbonyl]amino]-5-(trifluoromethyl)benzoic acid (0.89g). ¹H-NMR (300 MHz, d₄-MeOH): δ 8.59 (d, 1H, J=9.6 Hz), 8.26 (d, 1H,J=1.5 Hz), 7.72 (dd, 1H, J=9.2, 1.8 Hz), 3.23 (q, 2H, J=7.3 Hz), 1.17(t, 3H, J=7.2 Hz).

(63b) The 2-[[(ethylamino)carbonyl]amino]-5-(trifluoromethyl)benzoicacid (0.88 g, 3.2 mmol) was incorporated into procedure (47a) to provide1.2 (Z=—C(O)—, R²=2-(ethylaminocarbonyl)amino-5-(trifluoromethyl)benzoicacid, all other R=H, 0.70 g) as a white solid. ¹H-NMR (300 MHz,d₄-MeOH): δ 8.46 (d, 1H, J=8.8 Hz), 7.95 (d, 1H, J=1.1 Hz), 7.68 (dd,1H, J=8.9, 1.6 Hz), 4.09 (s, 2H), 3.22 (q, 2H, J=7.3 Hz), 1.15 (t, 3H,J=7.2 Hz).

(63c) The minor, (2S,3S)-diastereomer (63 mg, 0.17 mmol) from (61b) and1.2 (Z=—C(O)—, R²=2-(ethylaminocarbonyl)amino-5-(trifluoromethyl)phenyl,all other R=H; 55 mg, 0.17 mmol) were combined in procedure (1c). Theresultant product was taken through procedure (1d) and then purified byRP-HPLC to afford the title compound (1S,2S)-1.5 (l=m=0,R¹=2,4dimethylphenyl, R³=—CH(OH)n-propyl, Z=—C(O)—,R²=2-(ethylaminocarbonyl)amino-5-(trifluoromethyl)phenyl, all other R=H;28 mg). Exact MS calcd for C₂₈H₃₉F₃N₅O₄, the formula for(M+H)⁺=566.2954. Found: 566.2978.

Example 64N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(ethylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide

(64a) The major, (2S,3R)-diastereomer (100 mg, 0.26 mmol) from (61b) and1.2 (Z=—C(O)—, R²=2-(ethylaminocarbonyl)amino-5-(trifluoromethyl)phenyl,all other R=H; cf. procedure (63b); 91 mg, 0.26 mmol) were combined inprocedure (1c). The resultant product was taken through procedure (1d)and then purified by RP-HPLC to afford the title compound (1S,2R)-1.5(l=m 0, R¹=2,4-dimethylphenyl, R³=—CH(OH)n-propyl, Z=—C(O)—,R²=2-(ethylaminocarbonyl)amino-5-(trifluoromethyl)phenyl, all other R=H;50 mg). Exact MS calcd for C₂₈H₃₉F₃N₅O₄, the formula for(M+H)⁺=566.2954. Found: 566.2959.

Example 65N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(isopropylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide

(65a) Isopropylamine was incorporated into procedure (63a) to afford2-[[(isopropylamino)carbonyl]amino]-5-(trifluoromethyl)benzoic acid,which was then carried through procedure (63b) to afford 1.2 (Z=—C(O)—,R²=2-(isopropylaminocarbonyl)amino-5-(trifluoromethyl)phenyl, all otherR=H). This material (59 mg, 0.17 mmol) and the minor,(2S,3S)-diastereomer (65 mg, 0.17 mmol) from (61b) were combined inprocedure (1c). The resultant product was taken through procedure (1d)and then purified by RP-HPLC to afford the title compound (1S,2S)-1.5(l=m=0, R¹=2,4-dimethylphenyl, R³=—CH(OH)n-propyl, Z=—C(O)—,R²=2-(isopropylaminocarbonyl)amino-5-(trifluoromethyl)phenyl, all otherR=H; 30 mg). Exact MS calcd for C₂₉H₄₁F₃N₅O₄, the formula for(M+H)⁺=580.3111. Found: 580.3116.

Example 66N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(isopropylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide

(66a) The major, (2S,3R)-diastereomer (100 mg, 0.26 mmol) from (61b) and1.2 (Z=—C(O)—,R²=2-(isopropylaminocarbonyl)amino-5-(trifluoromethyl)phenyl, all otherR=H; cf. procedure (65a); 92 mg, 0.26 mmol) were combined in procedure(1c). The resultant product was taken through procedure (1d) and thenpurified by RP-HPLC to afford the title compound (1S,2R)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R³=—CH(OH)n-propyl, Z=—C(O)—,R²=2-(isopropylaminocarbonyl)amino-5-(trifluoromethyl)phenyl, all otherR=H; 30 mg). Exact MS calcd for C₂₉H₄₁F₃N₅O₄, the formula for(M+H)⁺=580.3111. Found: 580.3113.

Example 67N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[(1-pyrrolidinylcarbonyl)amino]-5-(trifluoromethyl)benzamide

(67a) Pyrrolidine was incorporated into procedure (63a) to afford2-[(1-pyrrolidinylcarbonyl)amino]-5-(trifluoromethyl)benzoic acid, whichwas then carried through procedure (63b) to afford 1.2 (Z=—C(O)—,R²=2-(1-pyrrolidinylcarbonyl)amino-5-(trifluoromethyl)phenyl, all otherR=H). This material (93 mg, 0.26 mmol) and the minor,(2S,3S)-diastereomer (98 mg, 0.26 mmol) from (61b) were combined inprocedure (1c). The resultant product was taken through procedure (1d)and then purified by RP-HPLC to afford the title compound (1S,2S)-1.5(l=m=0, R¹=2,4-dimethylphenyl, R³=—CH(OH)n-propyl, Z=—C(O)—,R²=2-(1-pyrrolidinylcarbonyl)amino-5-(trifluoromethyl)phenyl, all otherR=H; 10 mg). Exact MS calcd for C₃₀H₄₁F₃N₅O₄, the formula for(M+H)⁺=592.3111. Found: 592.3133.

Example 68N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[(1-azetidinylcarbonyl)amino]-5-(trifluoromethyl)benzamide

(68a) A cooled (0° C.) solution of the Weinreb amide (S)-11.2 (l=m=0,PGN=CbzHN, all other R=H, 5.27 g, 13.8 mmol) in THF (20 mL) was treatedwith propynylmagnesium bromide (110 mL of a 0.5 M solution in THF). Thereaction was stirred at RT for 3 h and recooled to 0° C. before beingquenched with the addition of sat. NH₄Cl. The reaction was diluted withH₂O and extracted with EtOAc (2×). The organic phase was washed withbrine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Theresultant ketone was dissolved in THF (2 mL) and treated with (R)-AlpineBorane (Aldrich Chemical Co.; 5.5 mL of neat liquid). The reaction wasstirred for 7 days at RT, concentrated in vacuo, and treated withethanolamine (1.2 mL). After stirring for 10 min at RT, the residue wasdiluted with Et₂O and the resultant solid was removed by suctionfiltration. The solution was concentrated in vacuo and the residue waspurified by flash chromatography (SiO₂) to provide (2S,3S)-11.5 (1=m=0,PGN=CbzHN, R=propynyl, all other R=H) as a yellow oil. MS found:(M+Na)⁺=385.3.

(68b) Azetidine was incorporated into procedure (63a) to afford2-[(1-azetidinylcarbonyl)amino]-5-(trifluoromethyl)benzoic acid, whichwas then carried through procedure (63b) to afford 1.2 (Z=—C(O)—,R²=2-(1-azetidinylcarbonyl)amino-5-(trifluoromethyl)phenyl, all otherR=H). This material (61 mg, 0.18 mmol) and (2S,3S)-11.5 (l=m=0,PGN=CbzHN, R=propynyl, all other R=H; cf. procedure (68a); 67 mg, 0.18mmol) were combined in procedure (1c). The resultant product was takenthrough procedure (1d) and then purified by RP-HPLC to afford the titlecompound (1S,2S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=—CH(OH)n-propyl,Z=—C(O)—, R²=2-(1-azetidinylcarbonyl)amino-5-(trifluoromethyl)phenyl,all other R=H; 10 mg). Exact MS calcd for C₂₉H₃₉F₃N₅O₄, the formula for(M+H)+578.2954. Found: 578.2977.

Example 69N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(methylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide

(69a) Methylamine was incorporated into procedure (63a) to afford2-[[(methylamino)carbonyl]amino]-5-(trifluoromethyl)benzoic acid, whichwas then carried through procedure (63b) to afford 1.2 (Z=—C(O)—,R²=2-(methylaminocarbonyl)amino-5-(trifluoromethyl)phenyl, all otherR=H). This material (56 mg, 0.18 mmol) and (2S,3S)-11.5 (l=m=0,PGN=CbzHN, R=propynyl, all other R=H; cf. procedure (68a); 67 mg, 0.18mmol) were combined in procedure (1c). The resultant product was takenthrough procedure (1d) and then purified by RP-HPLC to afford the titlecompound (1S,2S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=—CH(OH)n-propyl,Z=—C(O)—, R²=2-(methylaminocarbonyl)amino-5-(trifluoromethyl)phenyl, allother R=H; 5 mg). Exact MS calcd for C₂₇H₃₇F₃N₅O₄, the formula for(M+H)⁺=552.2798. Found: 552.2822.

Example 70N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(4-mopholinylcarbonyl)]amino]-5-(trifluoromethyl)benzamide

(70a) N-Boc glycine (36 mg, 0.21 mmol) and (2S,3S)-11.5 (l=m=0,PGN=CbzHN, R=propynyl, all other R=H; cf. procedure (68a); 78 mg, 0.21mmol) were combined in procedure (1c) to afford (1S,2S)-1.6 (l=m=0,PGN=CbzHN, R³=—CH(OH)n-propyl, all other R=H; 84 mg). MS found:(M+H)⁺=420.5.

(70b) Morpholine was incorporated into procedure (63a) to afford2-[(4-morpholinylcarbonyl)amino]-5-(trifluoromethyl)benzoic acid, aportion (69 mg, 0.18 mmol) of which which was then combined with(1S,2S)-1.6 (l=m=0, PGN=CbzHN, R³=—CH(OH)n-propyl, all other R=H; cf.procedure (70a); 69 mg, 0.18 mmol) and carried through procedure (1c). Aportion (32 mg, 0.06 mmol) of the resultant product was taken throughprocedure (1d) and then purified by RP-HPLC to afford the title compound(1S,2S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=—CH(OH)_(n)-propyl,Z=—C(O)—, R²=2-(4-morpholinylcarbonyl)amino-5-(trifluoromethyl)phenyl,all other R=H; 3 mg). Exact MS calcd for C₃₀H₄₁F₃N₅O₅, the formula for(M+H)⁺=608.3060. Found: 608.3048.

Example 71N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(1-piperazinylcarbonyl)]amino]-5-(trifluoromethyl)benzamide

(71a) piperazine was incorporated into procedure (63a) to afford2-[[(N-Boc 1-piperazinyl)carbonyl]amino]-5-(trifluoromethyl)benzoicacid, a portion (130 mg, 0.28 mmol) of which which was then combinedwith (1S,2S)-1.6 (l=m=0, PGN=CbzHN, R³=—CH(OH)n-propyl, all other R=H;cf. procedure (70a); 103 mg, 0.28 mmol) and carried through procedure(1c). The resultant product was taken through procedures (1d) and (48a),and then purified by RP-HPLC to afford the title compound (1S, 2S)-1.5(l=m=0, R¹=2,4-dimethylphenyl, R³=—CH(OH)n-propyl, Z=—C(O)—,R²=2-(1-piperazinylcarbonyl)amino-5-(trifluoromethyl)phenyl, all otherR=H; 3 mg). Exact MS calcd for C₃₀H₄₂F₃N₆O₄, the formula for(M+H)⁺=607.3220. Found: 607.3227.

Example 72N-[2-[[(1S,2S)-1-[[[(4-ethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide

(72a) The compound 1.2 (Z=—C(O)—, R²=N-Boc2-amino-5-(trifluoromethyl)benzoic acid, all other R=H; cf. procedure(47a); 68.4 mg, 0.26 mmol) and (2S,3S)-11.5 (1=m=0, PGN=CbzHN,R=propynyl, all other R=H; cf. procedure (68a); 110 mg, 0.30 mmol) werecombined in procedure (1c). A portion (24 mg, 0.05 mmol) of theresultant product was combined with para-ethylbenzaldehyde (0.007 mL,0.05 mmol) and taken through procedure (1d). The crude product waspurified by RP-HPLC to afford the title compound (1S,2S)-1.5 (l=m=0,R¹=4-ethylphenyl, R³=—CH(OH)n-propyl, Z=—C(O)—, R²=N-Boc2-amino-5-(trifluoromethyl)phenyl, all other R=H; 12 mg). Exact MS calcdfor C₃₀H₄₂F₃N₄O₅, the formula for (M+H)⁺=595.3107. Found: 595.3128.

Example 73N-[2-[[(1S,2S)-1-[[[(4-ethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide

(73a) A sample of (1S,2S)-1.5 (l=m=0, R¹=4-ethylphenyl,R³=—CH(OH)n-propyl, Z=—C(O)—, R²=N-Boc2-amino-5-(trifluoromethyl)phenyl, all other R=H; cf. procedure (72a); 8mg) was taken through procedure (48a). The residue was purified byRP-HPLC to afford the title compound (1S,2S)-1.5 (l=m=0,R¹=4-ethylphenyl, R³=—CH(OH)n-propyl, Z=—C(O)—,R²=2-amino-5-(trifluoromethyl)phenyl, all other R=H; 3 mg). Exact MScalcd for C₂₅H₃₄F₃N₄O₃, the formula for (M+H)⁺=495.2583. Found:495.2591.

Example 74N-[2-[[(1S,2S)-1-[[[(4-ethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(isopropylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide

(74a) The compound 1.2 (Z=—C(O)—,R²=2-(isopropylaminocarbonyl)amino-5-(trifluoromethyl)phenyl, all otherR=H; cf. procedure (65a); 0.93 g, 2.67 mmol) and (2S,3S)-11.5 (l=m=0,PGN=CbzHN, R=propynyl, all other R=H; cf. procedure (68a); 1.0 g, 2.76mmol) were combined in procedure (1c). A portion (52 mg, 0.11 mmol) ofthe resultant product was combined with 4-ethylbenzaldehyde (0.015 mL,0.11 mmol) and taken through procedure (1d). The crude product waspurified by RP-HPLC to afford the title compound (1S,2S)-1.5 (l=m=0,R¹=4-ethylphenyl, R³=—CH(OH)n-propyl, Z=—C(O)—,R²=2(isopropylaminocarbonyl)amino-5-(trifluoromethyl)phenyl, all otherR=H; 20 mg). Exact MS calcd for C₂₉H₄₁F₃N₅O₄, the formula for(M+H)⁺=580.3111. Found: 580.3131.

Example 75N-[2-[[(1S,2S)-1-[[[(4-ethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[(4-morpholinylcarbonyl)amino]-5-(trifluoromethyl)benzamide

(75a) The compound2-[(4-morpholinylcarbonyl)amino]-5-(trifluoromethyl)benzoic acid (cf.procedure (70b); 69 mg, 0.18 mmol) was combined with (1S,2S)-1.6 (l=m=0,PGN=CbzHN, R³=—CH(OH)n-propyl, all other R=H; cf. procedure (70a); 69mg, 0.18 mmol) and carried through procedure (1c). A portion (32 mg,0.06 mmol) of the resultant product was combined with4-ethylbenzaldehyde (0.009 mL, 0.06 mmol) and taken through procedure(1d). The crude product was purified by RP-HPLC to afford the titlecompound (1S,2S)-1.5 (l=m=0, R¹=4-ethylphenyl, R³=—CH(OH)n-propyl,Z=—C(O)—, R²=2-(4-morpholinylcarbonyl)amino-5-(trifluoromethyl)phenyl,all other R=H; 3 mg). MS found: (M+H)⁺=608.5.

Example 76N-[2-[[(1S,2S)-1-[[[(4-dimethylamino-2-methylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide

(76a) The compound 1.2 (Z=—C(O)—, R²=N-Boc2-amino-5-(trifluoromethyl)benzoic acid, all other R=H; cf. procedure(47a); 68.4 mg, 0.26 mmol) and (2S,3S)-11.5 (1=m=0, PGN=CbzHN,R=propynyl, all other R=H; cf. procedure (68a); 110 mg, 0.30 mmol) werecombined in procedure (1c). A portion (24 mg, 0.05 mmol) of theresultant product was combined with 4-dimethylamino-2-methylbenzaldehyde(8.3 mg, 0.05 mmol) and taken through procedure (1d). The crude productwas purified by RP-HPLC to afford the title compound (1S,2S)-1.5 (l=m=0,R¹=4-dimethylamino-2-methylphenyl, R³=—CH(OH)n-propyl, Z=—C(O)—,R²=N-Boc 2-amino-5-(trifluoromethyl)phenyl, all other R=H; 10 mg). MSfound: (M+H)⁺=624.6.

Example 77N-[2-[[(1S,2S)-1-[[[(4-dimethylamino-2-methylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide

(77a) A sample of (1S,2S)-1.5 (l=m=0, R¹=4-dimethylamino-2-methylphenyl,R³=—CH(OH)n-propyl, Z=—C(O)—, R²=N-Boc2-amino-5-(trifluoromethyl)phenyl, all other R=H; cf. procedure (76a); 7mg) was taken through procedure (48a). The residue was purified byRP-HPLC to afford the title compound (1S,2S)-1.5 (l=m=0,R¹=4-dimethylamino-2-methylphenyl, R³=—CH(OH)n-propyl, Z=—C(O)—,R²=2-amino-5-(trifluoromethyl)phenyl, all other R=H; 3 mg). Exact MScalcd for C₂₆H₃₇F₃N₅O₃, the formula for (M+H)⁺=524.2848. Found:524.2864.

Example 78N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2(hydroxy)pentyl]amino]-2-oxoethyl]-2-(tert-butyl)amino-5-(trifluoromethyl)benzamide

(78a) Allyl bromide (2.8 mL), [2-fluoro-5-(trifluoromethyl)]benzoic acid(5.5 g), and potassium carbonate (4.6 g) were dissolved in DMF (90 mL).The reaction was stirred for 12 h and diluted with water and EtOAc. Theorganic layer was washed with 2% LiCl solution, dried, filtered, andconcentrated to provide allyl [2-fluoro-5-(trifluoromethyl)] benzoate(6.4 g). This material was dissolved in DMF (25 mL) and the solution wascharged with tert-butylamine (16 mL) and potassium carbonate (7.4 g).The mixture was warmed to 40° C., stirred for 36 h, and diluted withwater and EtOAc. The organic layer was washed with 2% LiCl solution,dried, filtered and concentrated to provide allyl[2-(tert-butylamino)-5-(trifluoromethyl)]benzoate (7.6 g). This materialwas combined with pyrrolidine (2.3 mL) and dissolved in acetonitrile(150 mL). The solution was degassed with nitrogen, and thentetrakis(triphenylphosphino) palladium(0) was added. This mixture wasstirred for 8 h, and concentrated. The residue was dissolved in EtOAcand washed with 1 N HCl solution and water. The organic layer was dried,filtered, and concentrated. Flash chromatography of the resultingresidue provided 2-(tert-butylamino)-5-(trifluoromethyl)]benzoic acid(4.6 g). MS found: (M−H)⁻=260.2.

(78b) The 2-(tert-butylamino)-5-(trifluoromethyl)]benzoic acid wascarried through procedure (47a) to afford 1.2 (Z=—C(O)—,R²=2-(tert-butyl)amino-5-(trifluoromethyl)benzoic acid, all other R=H).A portion (56 mg, 0.18 mmol) of this material was combined with(2S,3S)-11.5 (l=m=0, PGN=CbzHN, R=propynyl, all other R=H; cf. procedure(68a); 67 mg, 0.18 mmol) and incorporated in procedure (1c). The productwas carried through procedure (1d). The crude product was purified byRP-HPLC to afford the title compound (1S, 2S)-1.5 (l=m=0,R¹=4-ethylphenyl, R³=—CH(OH)_(n)-propyl, Z=—C(O)—,R²=2-(tert-butyl)amino-5-(trifluoromethyl)phenyl, all other R=H; 10 mg).Exact MS calcd for C₂₉H₄₂F₃N₄O₃, the formula for (M+H)⁺=551.3209. Found:551.3225.

Example 79N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-isopropylamino-5-(trifluoromethyl)benzamide

(79a) Isopropylamine (4.0 mL) was dissolved in THF (20 mL). Thissolution was cooled to 0° C. and n-butyllithium (2.5 M, 20 mL) wasadded. The reaction was stirred for 90 min and then transferred to asolution of 2-fluoro-5-(trifluoromethyl)benzoic acid (4.2 g) in THF (40mL) at-78° C. This mixture was stirred for 15 min and then quenched withaqueous NH₄Cl. The mixture was extracted with EtOAc (3×), and theorganic layer was dried, filtered, and concentrated in vacuo. Flashchromatography of the resulting residue provided2-isopropylamino-5-(trifluoromethyl)benzoic acid (2.4 g). MS found:(M+H)⁺=248.2.

(79b) The 2-isopropylamino-5-(trifluoromethyl)]benzoic acid was carriedthrough procedure (47a) to afford 1.2 (Z=—C(O)—,R²=2-isopropylamino-5-(trifluoromethyl)benzoic acid, all other R=H). Aportion (61 mg, 0.18 mmol) of this material was combined with(2S,3S)-11.5 (l=m=0, PGN=CbzHN, R=propynyl, all other R=H; cf. procedure(68a); 67 mg, 0.18 mmol) and incorporated in procedure (1c). The productwas carried through procedure (1d). The crude product was purified byRP-HPLC to afford the title compound (1S, 2S)-1.5 (l=m=0,R¹=4-ethylphenyl, R³=—CH(OH)_(n)-propyl, Z=—C(O)—,R²=2-isopropylamino-5-(trifluoromethyl)phenyl, all other R=H; 10 mg).Exact MS calcd for C₂₈H₄₀F₃N₄O₃, the formula for (M+H)⁺=537.3053. Found:537.3074.

Example 80N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-benzylamino-5-(trifluoromethyl)benzamide

(80a) N-Boc 2-amino-5-(trifluoromethyl)benzoic acid (S. Takagishi, etal., Synlett 1992, 360; 3.0 g) was dissolved in DMF prior to theaddition of K₂CO₃ (2.4 g) and iodomethane (0.8 mL). After 1.5 h, thesolution was diluted with EtOAc and was washed with brine solutionfollowed by 1N HCl solution. The organic layer was then washed withNa₂CO₃ solution, water, and brine. The organic layer was dried (MgSO₄),filtered, and concentrated to give the ester as an off-white solid (3.03g). A portion of this solid was dissolved in TFA (3.3 mL) and cooled to0° C. prior to the addition of TFAA (0.97 mL). After 10 min, crushed icewas added. After an additional 30 min, the solid was collected andwashed with water. The solid was dried to give the TFA amide (970 mg). Aportion of this solid (583 mg) was dissolved in DMF (12 mL), and thesolution was charged with K₂CO₃ (511 mg) and benzyl bromide (0.24 mL).The reaction was stirred 18 h before it was diluted with EtOAc andwashed with 1N HCl and brine. The EtOAc was dried (MgSO₄), filtered, andconcentrated in vacuo. The resulting residue was dissolve in THF (10 mL)prior to addition of 1N LiOH (10 mL) and 20 drops of MeOH. After 18 h,the THF was removed and the solution was made acidic (pH=5) with 1N HCl.This solution was extracted with EtOAc. The organic layer was washedwith brine, dried, filtered, and concentrated to give2-benzylamino-5-trifluoromethylbenzoic acid (500 mg). MS found:(2M−H)⁻=589.1.

(80b) The compound from procedure (80a),2-benzylamino-5-(trifluoromethyl)benzoic acid (58 mg, 0.20 mmol), wascombined with (1S,2S)-1.6 (l=m=0, PGN=CbzHN, R³=—CH(OH)n-propyl, allother R=H; cf. procedure (70a); 64 mg, 0.20 mmol) and carried throughprocedures (1c) and (1d). The crude product was purified by RP-HPLC toafford the title compound (1S,2S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl,R³=—CH(OH)n-propyl, Z=—C(O)—,R²=2-benzylamino-5-(trifluoromethyl)phenyl, all other R=H; 5 mg). MSfound: (M+H)⁺=585.6.

Example 81N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(methoxy)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide

(81a) To a cooled (0° C.), light-protected solution of (2S, 3S)-11.5(l=m=0, PGN=CbzHN, R=propynyl, all other R=H; cf. procedure (68a); 0.27g, 0.75 mmol) in methylene chloride (8 mL) was added Me₃OBF₃ (0.15 g,1.0 mmol) and then proton sponge (0.21 g, 0.98 mmol). The reaction wasstirred for 2 days in the dark and then diluted with methylene chlorideand filtered through a pad of Celite. The filtrate was washed with 1NHCl (2×) and brine (1×), and then dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was purified via flash chromatography(SiO₂) to afford the desired (2S, 3S)-11.6 (l=m=0, PGN=CbzHN,R=propynyl, R′=Me, all other R=H; 49 mg). MS found: (M+Na)⁺=399.4.

(81b) The compound 1.2 (Z=—C(O)—, R²=N-Boc2-amino-5-(trifluoromethyl)benzoic acid, all other R=H; cf. procedure(47a); 54 mg, 0.15 mmol) and (2S,3S)-11.6 (1=m=0, PGN=CbzHN, R=propynyl,R′=Me, all other R=H; cf. procedure (81a); 49 mg, 0.13 mmol) werecombined in procedure (1c). The product was taken through procedure(1d), and the resultant product was purified by RP-HPLC to afford thetitle compound (1S,2S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl,R³=—CH(OMe)n-propyl, Z=—C(O)—, R²=N-Boc2-amino-5-(trifluoromethyl)phenyl, all other R=H; 15 mg). Exact MS calcdfor C₃₁H₄₄F₃N₄O₅, the formula for (M+H)⁺=609.3264. Found: 609.3270.

Example 82N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(methoxy)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide

(82a) A sample of (1S,2S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl,R³=—CH(OMe)n-propyl, Z=—C(O)—, R²=N-Boc2-amino-5-(trifluoromethyl)phenyl, all other R=H; 11 mg) from procedure(81b) was taken through procedure (48a). The resultant product waspurified by RP-HPLC to afford the title compound (1S,2S)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R³=—CH(OMe)n-propyl, Z=—C(O)—,R²=2-amino-5-(trifluoromethyl)phenyl, all other R=H; 10 mg). MS found:(M+H)⁺=509.5.

Example 83N-[2-[[(S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(methyl)propyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide

(83a) To a cooled (−78° C.) solution of the Weinreb amide (S)-11.2(l=m=0, PGN=CbzHN, all other R=H, 0.26 g, 0.69 mmol) in THF (7 mL) wasadded methyl lithium (4.0 mL of a 1.0 M solution in THF). The reactionwas stirred for 2 h at −78° C. and 30 min at RT. The mixture wasrecooled to −78° C. and quenched with sat. NH₄Cl. The mixture wasdiluted with EtOAc, washed with sat. NH₄Cl (2 x) and brine (1×), anddried (Na₂SO₄), filtered, and concentrated in vacuo. The residue wasresubjected to the identical procedure, including the aqueous workup,and the resultant residue was purified by flash chromatography to affordthe desired (S)-11.4 (l=m=0, PGN=CbzHN, R=R″=methyl, all other R=H; 74mg). MS found: (M+Na)⁺=375.4.

(83b) The compound 1.2 (Z=—C(O)—, R²=N-Boc2-amino-5-(trifluoromethyl)benzoic acid, all other R=H; cf. procedure(47a); 88 mg, 0.24 mmol) and (S)-11.4 (l=m=0, PGN=CbzHN, R=R″=methyl,all other R=H; cf. procedure (83a); 74 mg, 0.21 mmol) were combined inprocedure (1c). The product was taken through procedure (1d), and theresultant product was purified by RP-HPLC to afford the title compound(S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=—C(OH)Me₂, Z=—C(O)—, R²=N-Boc2-amino-5-(trifluoromethyl)phenyl, all other R=H; 10 mg). Exact MS calcdfor C₂₉H₄₀F₃N₄O₅, the formula for (M+H)⁺=581.2951. Found: 581.2940.

Example 84N-[2-[[(S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(methyl)propyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide

(84a) A sample of (S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=—C(OH)Me₂,Z=—C(O)—, R²=N-Boc 2-amino-5-(trifluoromethyl)phenyl, all other R=H; 11mg) from procedure (83b) was taken through procedure (48a). Theresultant product was purified by RP-HPLC to afford the title compound(S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=—C(OH)Me₂, Z=—C(O)—,R²=2-amino-5-(trifluoromethyl)phenyl, all other R=H; 10 mg). MS found:(M+H)⁺=481.4.

Example 85N-[2-[[(S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(ethyl)butyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide

(85a) To a cooled (0° C.) solution of Weinreb amide (S)-11.2 (l=m=0,PGN=CbzHN, all other R=H, 0.25 g, 0.66 mmol) in THF (7 mL) was addedethylmagnesium bromide (2.0 mL of a 2.0 M solution in THF). The reactionwas stirred for 3 h in the melting ice bath (during which time it warmsto RT). The mixture was recooled to 0° C. and quenched with sat. NH₄Cl.The mixture was diluted with EtOAc, washed with sat. NH₄Cl (2×) andbrine (1×), and dried (Na₂SO₄), filtered, and concentrated in vacuo. Theresidue was resubjected to the identical procedure, including theaqueous workup, and the resultant residue was purified by flashchromatography to afford the desired (S)-11.4 (l=m=0, PGN=CbzHN,R=R″=ethyl, all other R=H; 125 mg).

(85b) The compound 1.2 (Z=—C(O)—, R²=N-Boc2-amino-5-(trifluoromethyl)benzoic acid, all other R=H; cf. procedure(47a); 140 mg, 0.39 mmol) and (S)-11.4 (l=m=0, PGN=CbzHN, R=R″=ethyl,all other R=H; cf. procedure (85a); 125 mg, 0.33 mmol) were combined inprocedure (1c). The product was taken through procedure (1d), and theresultant product was purified by RP-HPLC to afford the title compound(S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=—C(OH)Et₂, Z=—C(O)—, R²=N-Boc2-amino-5-(trifluoromethyl)phenyl, all other R=H; 10 mg). Exact MS calcdfor C₃₁H₄₄F₃N₄O₅, the formula for (M+H)⁺=609.3264. Found: 609.3291.

Example 86N-[2-[[(S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(ethyl)butyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide

(86a) A sample of (S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=—C(OH)Et₂,Z=—C(O)—, R²=N-Boc 2-amino-5-(trifluoromethyl)phenyl, all other R=H; 11mg) from procedure (85b) was taken through procedure (48a). Theresultant product was purified by RP-HPLC to afford the title compound(S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=—C(OH)Et₂, z=—C(O)—,R²=2-amino-5-(trifluoromethyl)phenyl, all other R=H; 5 mg). MS found:(M+H)⁺=509.4.

Example 87N-[2-[[(S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(propyl)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide

(87a) To a cooled (0° C.) solution of Weinreb amide (S)-11.2 (l=m=0,PGN=CbzHN, all other R=H, 1.07 g, 2.8 mmol) in THF (25 mL) was addedallylmagnesium bromide (17.0 mL of a 1.0 M solution in THF). Thereaction was stirred for 3 h in the melting ice bath (during which timeit warms to RT). The mixture was recooled to 0° C. and quenched withsat. NH₄Cl. The mixture was diluted with EtOAc, washed with sat. NH₄Cl(2×) and brine (1×), and dried (Na₂SO₄), filtered, and concentrated invacuo. The residue was resubjected to the identical procedure, includingthe aqueous workup, and the resultant residue was purified by flashchromatography to afford the desired (S)-11.4 (l=m 0, PGN=CbzHN,R=R″=allyl, all other R=H; 560 mg). MS found: (M+Na)⁺=427.4.

(87b) The compound 1.2 (Z=—C(O)—, R²=N-Boc2-amino-5-(trifluoromethyl)benzoic acid, all other R=H; cf. procedure(47a); 176 mg, 0.49 mmol) and (2S,3S)-11.4 (1=m=0, PGN=CbzHN,R=R″=allyl, all other R=H; cf. procedure (87a); 137 mg, 0.45 mmol) werecombined in procedure (1c). The product was taken through procedure(1d), and the resultant product was purified by RP-HPLC to afford thetitle compound (S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=—C(OH)n-Pr₂,Z=—C(O)—, R²=N-Boc 2-amino-5-(trifluoromethyl)phenyl, all other R=H; 10mg). MS found: (M+H)⁺=637.6.

Example 88N-[2-[[(S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(propyl)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide

(88a) A sample of (S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=—C(OH)n-Pr₂,Z=—C(O)—, R²=N-Boc 2-amino-5-(trifluoromethyl)phenyl, all other R=H; 11mg) from procedure (87b) was taken through procedure (48a). Theresultant product was purified by RP-HPLC to afford the title compound(S)-1.5 (l=m=0, R¹=2,4dimethylphenyl, R³=—C(OH)n-Pr₂, Z=—C(O)—,R²=2-amino-5-(trifluoromethyl)phenyl, all other R=H; 5 mg). Exact MScalcd for C₂₈H₄₀F₃N₄O₃, the formula for (M+H)⁺=537.3053. Found:537.3065.

Example 89N-[2-[[(S)-2-[[(2,4-dimethylphenyl)methyl]amino]-1-(hydroxycyclopentyl)ethyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide

(89a) To a solution of (S)-11.4 (l=m=0, PGN=CbzHN, R=R″=allyl, all otherR=H; 140 mg) in methylene chloride (4 mL) was addedtricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidene]ruthenium (IV) dichloride (Strem, Inc.; ca. 2 mg, catalyticamount). The reaction was stirred for 12 h at RT before beingconcentrated in vacuo. The residue was purified by flash chromatographyto provide (S)-11.4 (l=m=0, PGN=CbzHN, R=R″=—CH₂C═CCH₂—, all other R=H;31 mg). MS found: (M+H)⁺=399.4.

(89b) The compound 1.2 (Z=—C(O)—, R²=N-Boc2-amino-5-(trifluoromethyl)benzoic acid, all other R=H; cf. procedure(47a); 92 mg, 0.25 mmol) and (S)-11.4 (l=m=0, PGN=CbzHN,R=R″=—CH₂C═CCH₂—, all other R=H; cf. procedure (89a); 59 mg, 0.16 mmol)were combined in procedure (1c). The product was taken through procedure(1d), and the resultant product was purified by RP-HPLC to afford thetitle compound (S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=—C(OH)c-C₄H₈,Z=—C(O)—, R²=N-Boc 2-amino-5-(trifluoromethyl)phenyl, all other R=H; 15mg). MS found: (M+H)⁺=607.5.

Example 90N-[2-[[(S)-1-[[(S)-2-[[(2,4-dimethylphenyl)methyl]amino]-1-(hydroxycyclopentyl)ethyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide

(90a) A sample of (S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl,R³=—C(OH)c-C₄H₈, Z=—C(O)—, R²=N-Boc 2-amino-5-(trifluoromethyl)phenyl,all other R=H; 10 mg) from procedure (89b) was taken through procedure(48a). The resultant product was purified by RP-HPLC to afford the titlecompound (S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³=—C(OH)c-C₄H₈,Z=—C(O)—, R²=2-amino-5-(trifluoromethyl)phenyl, all other R=H; 3 mg).Exact MS calcd for C₂₆H₃₄F₃N₄O₃, the formula for (M+H)⁺=507.2583. Found:507.2588.

Example 91(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethoxy)benzoyl]amino]acetyl]amino]-propanamide

(91a) The compound (S)-1.6 (l=m=0, PGN=CbzHN, R³═CONHt-Bu, all otherR=H; cf. procedure (33b); 1.4 g, 3.1 mmol) was incorporated intoprocedure (1d). The resultant secondary amine (1.1 g, 2.6 mmol) wasdissolved in THF (39 mL). The solution was charged with triethylamine(0.69 mL, 5.2 mmol) and dibenzyldicarbonate (893 mg, 3.1 mmol) andstirred for 48 h before being concentrated in vacuo. The residue wasdissolved in EtOAc, and the solution was washed successively with 1NHCl, water, and brine. The organic phase was dried (Na₂SO₄), filtered,and concentrated in vacuo to give (S)-1.6 (l=m=0, PGN=2,4-Me₂Ph(Cbz)N,R³=CONHt-Bu, all other R=H, 0.7 g). MS found: (M+H)⁺=569.3.

(91b) A solution of (S)-1.6 (l=m=0, PGN=2,4-Me₂Ph(Cbz)N, R³=CONHt-Bu,all other R=H; 65 mg, 0.14 mmol) in DMF (3 mL) was charged successivelywith 3-trifluoromethoxybenzoic acid (29 mg, 0.14 mmol),N,N-diisopropylethylamine (0.06 mL, 0.35 mmol), and HATU (63 mg, 0.17mmol). The mixture was stirred for 12 h and diluted with EtOAc. Theorganic phase was washed with water (2×), sat. NaHCO₃, water, and brine.The organic phase was then dried (Na₂SO₄), filtered, and concentrated invacuo. The product was dissolved in MeOH (2 mL) and the solution wascharged with 5% Pd/C, Degussa (13 mg). The reaction vessel was evacuatedand back-filled with hydrogen several times over the course of 4 h. Themixture was filtered and the filtrate was concentrated in vacuo.Purification by RP-HPLC afforded the title compound (S)-1.5(R¹=2,4-dimethylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=3-trifluoromethoxyphenyl, all other R=H; 3 mg). Exact MS calcd forC₂₆H₃₄F₃N₄O₄, the formula for (M+H)⁺=523.2532. Found: 523.2521.

Example 92(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(difluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(92a) A solution of meta-cyanobenzaldehyde (1.3 g, 10 mmol) in methylenechloride (30 mL) was charged with DAST (1.3 mL, 10 mmol) and stirred for3 h at RT. The mixture was poured into water and extracted withmethylene chloride (2×). The organic extracts were combined, washed withbrine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Theresultant 3-difluoromethyl-benzonitrile was dissolved in dioxane (15 mL)and 6N HCl (20 mL) and heated at 100° C. for 18 h. The mixture wascooled to RT and extracted with EtOAc (2×). The organic extracts werewashed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuo.Analysis by ¹H-NMR showed 45% conversion to the benzoic acid. Theresidue was dissolved in Et₂O and washed with 1N NaOH. The organic layerwas discarded; the aqueous layer was acidified with 12M HCl andextracted with EtOAc (2×). The organic extracts were combined, washedwith brine, dried (Na₂SO₄), filtered, and concentrated in vacuo toprovide pure 3-(difluoromethyl)benzoic acid as a white solid (459 mg).

(92b) The compound 3-(difluoromethyl)benzoic acid (52 mg) wasincorporated into procedure (91b). A portion (13.5 mg) of the resultantproduct was dissolved in ethanol (0.2 mL) and the solution was chargedwith 10% Pd/C (7 mg) and cyclohexene (0.01 mL). The reaction mixture washeated at 80° C. for 30 min, cooled to RT, and filtered. The filtratewas concentrated in vacuo. Purification by RP-HPLC afforded the titlecompound (S)-1.5 (R¹ 2,4-dimethylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—, R²3-difluoromethylphenyl, all other R=H; 5 mg). Exact MS calcd forC₂₆H₃₅F₂N₄O₃, the formula for (M+H)⁺=489.2677. Found: 489.2665.

Example 93(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethylthio)benzoyl]amino]acetyl]amino]-propanamide

(93a) The compound 3-(trifluoromethylthio)benzoic acid (25 mg, 0.11mmol) was incorporated into procedure (91b). Purification by RP-HPLCafforded the title compound (S)-1.5 (R¹=2,4-dimethylphenyl,R³=—C(O)NHt-Bu, Z=—C(O)—R²=3-(F₃CS)phenyl, all other R=H; 5 mg). ExactMS calcd for C₂₆H₃₄S₁F₃N₄O₃, the formula for (M+H)⁺=539.2304. Found:539.2292.

Example 94(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(pentafluoroethyl)benzoyl]amino]acetyl]amino]-propanamide

(94a) Methyl 3-iodobenzoate (1.0 g) was dissolved in DMF (10 mL) andtoluene (4 mL) prior to the addition of CuI (1.34 g) and CF₃CF₂CO₂Na(1.45 g). This mixture was heated at 130° C. and some toluene wasremoved via a Dean-Stark trap (Freskos, J. Syn Comm. 1988, 965). Themixture was then heat at 155° C. for 2 h. After cooling the solution waspoured into water and Et₂O. The organic layer was dried andconcentrated. The resulting residue was dissolved in THF (6 mL) and MeOH(1 mL) prior to the addition of 1M LiOH/H₂O solution (9.3 mL). After 3h, the solution was partially concentrated. The reaction was quenchedwith 1N HCl solution and extracted with EtOAc. The organic layer wasdried and concentrated in vacuo. MS found: (M−H)⁻=239.1.

(94b) The compound 3-(pentafluoroethyl)benzoic acid (29 mg, 0.12 mmol)was incorporated into procedure (91b). Purification by RP-HPLC affordedthe title compound (S)-1.5 (R¹=2,4-dimethylphenyl, R³=—C(O)NHt-Bu,Z=—C(O)—, R²=3-(pentafluoroethyl)phenyl, all other R=H; 5 mg). Exact MScalcd for C₂₇H₃₄F₅N₄O₃, the formula for (M+H)⁺=557.2551. Found:557.2524.

Example 95(2S)-N-tert-Butyl-2-[[[[2-amino-5-(trifluoromethoxy)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(95a) A cooled (−78° C.) solution of para-(trifluoromethoxy)aniline (3.2mL, 24 mmol) in THF (200 mL) was charged with NaHMDS (53 mL of a 1.0 MTHF solution) and stirred for 1 h. The mixture was then charged with asolution of di-(tert-butyl)dicarbonate (5.3 g, 24 mmol) in THF (40 mL)and stirred for 14 h, during which time it slowly warmed to RT. Thereaction was concentrated in vacuo and the residue was dissolved inEtOAc. The organic phase was washed successively with 1N HCl, water, andbrine before being dried (Na₂SO₄), filtered, and concentrated in vacuoto provide N-Boc para-(trifluoromethoxy)aniline (6.2 g). The entirity ofthis product was dissolved in THF (112 mL), and the resultant solutionwas cooled to −78° C. before being charged with sec-butyllithium (38 mLof a 1.3 M solution). The solution was warmed to −40° C. and stirred atthat temperature for 3 h. The reaction vessel was then evacuated andback-filled with carbon dioxide. The mixture was stirred for 14 h,during which time it slowly warmed to RT. The mixture was then treatedwith 1N HCl, stirred for 10 min, and extracted with EtOAc (2×). Theorganic extracts were washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The residue was purified by flash chromatographyto afford N-Boc 2-amino-3-(trifluoromethoxy)benzoic acid (3.4 g).

(95b) A solution of (S)-1.6 (l=m=0, PGN 2,4-Me₂Ph(Cbz)N, R³=CONHt-Bu,all other R=H; cf. procedure (91a); 55 mg, 0.12 mmol) in 1:1 methylenechloride/DMF (3 mL) was charged successively with N-Boc2-amino-3-(trifluoromethoxy)benzoic acid (37 mg, 0.12 mmol),N,N-diisopropylethylamine (0.05 mL, 0.21 mmol), and HATU (53 mg, 0.14mmol). The mixture was stirred for 12 h and diluted with EtOAc. Theorganic phase was washed with water (2×), sat. NaHCO₃, water, and brine.The organic phase was then dried (Na₂SO₄), filtered, and concentrated invacuo. The product was carried through procedure (48a) to provide(S)-1.5 (R¹=2,4-dimethylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=2-amino-3-(trifluoromethoxy)phenyl, all other R=H; 15 mg) afterpurification by RP-HPLC. MS found: (M+H)⁺=672.3.

(95c) A sample of (S)-1.5 (R¹=2,4-dimethylphenyl, R³=—C(O)NHt-Bu,Z=—C(O)—, R²=2-amino-3-(trifluoromethoxy)phenyl, all other R=H; 15 mg)was dissolved in MeOH (2 mL) and the solution was charged with 5% Pd/C,Degussa (13 mg). The reaction vessel was evacuated and back-filled withhydrogen several times over the course of 4 h. The mixture was filteredand the filtrate was concentrated in vacuo. Purification by RP-HPLCafforded the title compound (S)-1.5 (R¹=2,4-dimethylphenyl,R³=—C(O)NHt-Bu, Z=—C(O)—, R²=2-amino-3-(trifluoromethoxy)phenyl, allother R=H; 4 mg). Exact MS calcd for C₂₆H₃₅F₃N₅O₄, the formula for(M+H)⁺=538.2641. Found: 538.2644.

Example 96(2S)-N-tert-Butyl-2-[[[[2-amino-5-(methyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(96a) The compound 2-amino-5-(methyl)benzoic acid (65 mg, 0.14 mmol) wasincorporated into procedure (91b). Purification by RP-HPLC afforded thetitle compound (S)-1.5 (R¹=2,4-dimethylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=2-amino-5-(methyl)phenyl, all other R=H; 5 mg). Exact MS calcd forC₂₆H₃₈N₅O₃, the formula for (M+H)+468.2975. Found: 468.3002.

Example 97(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-ethylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(97a) Iodoethane was incorporated into procedure (80a) to afford2-ethylamino-5-trifluoromethylbenzoic acid, a portion (52 mg, 0.11 mmol)of which was incorporated into procedure (91b). Purification by RP-HPLCafforded the title compound (S)-1.5 (R¹=2,4-dimethylphenyl,R³—C(O)NHt-Bu, Z=—C(O)—, R²=2-ethylamino-5-(trifluoromethyl)phenyl, allother R=H; 5 mg). Exact MS calcd for C₂₈H₃₉F₃N₅O₃, the formula for(M+H)⁺=550.3005. Found: 550.3013.

Example 98(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-propylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(98a) Allyl iodide was incorporated into procedure (80a) to afford2-allylamino-5-trifluoromethylbenzoic acid, a portion (20 mg, 0.08 mmol)of which was incorporated into procedure (91b). Purification by RP-HPLCafforded the title compound (S)-1.5 (R¹=2,4-dimethylphenyl,R³—C(O)NHt-Bu, Z=—C(O)—, R²=2-propylamino-5-(trifluoromethyl)phenyl, allother R=H; 5 mg). Exact MS calcd for C₂₉H₄₁F₃N₅O₃, the formula for(M+H)⁺=564.3161. Found: 564.3187.

Example 99(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-isobutylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(99a) The compound 2-methylpropenyl bromide was incorporated intoprocedure (80a) to afford 2-(methylpropenyl)amino-5-(trifluoromethyl)benzoic acid, a portion (17 mg, 0.07 mmol) of which was incorporatedinto procedure (91b). Purification by RP-HPLC afforded the titlecompound (S)-1.5 (R¹=2,4-dimethylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=2-isobutylamino-5-(trifluoromethyl)phenyl, all other R=H; 5 mg).Exact MS calcd for C₃₀H₄₃F₃N₅O₃, the formula for (M+H)⁺=578.3318. Found:578.3300.

Example 100(2S)-N-tert-Butyl-2-[[[[2-butylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(100a) Butyl iodide was incorporated into procedure (80a) to afford2-butylamino-5-(trifluoromethyl) benzoic acid, a portion (18 mg, 0.095mmol) of which was incorporated into procedure (91b). Purification byRP-HPLC afforded the title compound (S)-1.5 (R¹=2,4-dimethylphenyl,R³=—C(O)NHt-Bu, Z=—C(O)—, R²=2-butylamino-5-(trifluoromethyl)phenyl, allother R=H; 2 mg). Exact MS calcd for C₃₀H₄₃F₃N₅O₃, the formula for(M+H)⁺=578.3318. Found: 578.3325.

Example 101(2S)-N-tert-Butyl-2-[[[[2-cyclohexylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(101a) Cyclohexylamine was incorporated into procedure (79a) to provide2-cyclohexylamino-5-(trifluoromethyl)benzoic acid, which was carriedthrough procedure (47a) to afford 1.2 (Z=—C(O)—,R²=2-(methylaminocarbonyl)amino-5-(trifluoromethyl)phenyl, all otherR=H). A portion (59 mg, 0.19 mmol) of this material was combined with(S)-2.3 (l=m=0, —C(O)N(R^(3a))₂=—C(O)NHt-Bu; cf. procedure (33a); 75 mg,0.19 mmol) in procedure (1c). The product was carried through procedure(1d). The resultant crude product was purified by RP-HPLC to afford thetitle compound (S)-1.5 (R¹=2,4-dimethylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=2-cyclohexylamino-5-(trifluoromethyl)phenyl, all other R=H; 10 mg).Exact MS calcd for C₃₂H₄₅F₃N₅O₃, the formula for (M+H)⁺=604.3474. Found:604.3452.

Example 102(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-isopropylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(102a) The compounds (S)-2.3 (l=m=0, —C(O)N(R^(3a))₂=—C(O)NHt-Bu; cf.procedure (33a); 75 mg, 0.19 mmol) and 1.2 (Z=—C(O)—,R²=2-isopropylamino-5-(trifluoromethyl)phenyl, all other R=H; cf.procedure (79b); 59 mg, 0.19 mmol) were combined in procedure (1c), andthe product was taken through procedure (1d). The resultant crudeproduct was purified by RP-HPLC to afford the title compound (S)-1.5(R¹=2,4-dimethylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=2-isopropylamino-5-(trifluoromethyl)phenyl, all other R=H; 10 mg).Exact MS calcd for C₂₉H₄₁F₃N₅O₃, the formula for (M+H)⁺=564.3161. Found:564.3172.

Example 103(2S)—N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-(tert-butyl)amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(103a) The compounds (S)-2.3 (l=m=0, —C(O)N(R^(3a))₂=—C(O)NHt-Bu; cf.procedure (33a); 75 mg, 0.19 mmol) and 1.2 (Z=—C(O)—,R²=2-(tert-butyl)amino-5-(trifluoromethyl)phenyl, all other R=H; cf.procedure (78b); 59 mg, 0.19 mmol) were combined in procedure (1c), andthe product was taken through procedure (1d). The resultant crudeproduct was purified by RP-HPLC to afford the title compound (S)-1.5(R¹=2,4-dimethylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=2-(tert-butyl)amino-5-(trifluoromethyl)phenyl, all other R=H; 5 mg).Exact MS calcd for C₃₀H₄₃F₃N₅O₃, the formula for (M+H)⁺=578.3318. Found:578.3319.

Example 104(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-(methylaminocarbonyl)amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(104a) The compounds (S)-2.3 (l=m=0, —C(O)N(R^(3a))₂=—C(O)NHt-Bu; cf.procedure (33a); 75 mg, 0.19 mmol) and 1.2 (Z=—C(O)—,R²=2-(methylaminocarbonyl)amino-5-(trifluoromethyl)phenyl, all otherR=H; cf. procedure (69a); 59 mg, 0.19 mmol) were combined in procedure(1c). The product was taken through procedure (1d). Purification byRP-HPLC afforded the title compound (S)-1.5 (R¹=2,4-dimethylphenyl,R³=—C(O)NHt-Bu,Z=—C(O)—R²=2-(methylaminocarbonyl)amino-5-(trifluoromethyl)phenyl, allother R=H; 10 mg). Exact MS calcd for C₂₈H₃₈F₃N₆O₄, the formula for(M+H)⁺=579.2907. Found: 579.2909.

Example 105(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-(isopropoxycarbonyl)amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(105a) 2-Amino-5-trifluoromethylbenzoic acid (110 mg) was dissolved in aTHF (4 mL), water (1 mL), and Et₃N (0.25 mL) mixture prior to theaddition of iso-propyl chloroformate (0.54 mL, 1M in toluene). Thesolution was stirred at rt for 18 h. The reaction was quenched with 1NHCl solution and extracted with EtOAc. The organic layer was dried(Na₂SO₄) and concentrated in vacuo.

(105b) The compound2-(isopropoxycarbonyl)amino-5-(trifluoromethyl)benzoic acid wasincorporated into procedure (91b). Purification by RP-HPLC afforded thetitle compound (S)-1.5 (R¹=2,4-dimethylphenyl, R³—C(O)NHt-Bu, Z=—C(O)—,R²=2-(isopropoxycarbonyl)amino-5-(trifluoromethyl)phenyl, all other R=H;5 mg). Exact MS calcd for C₃₀H₄₁F₃N₅O₅, the formula for (M+H)⁺=608.3060.Found: 608.3080.

Example 106(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-(isopropylaminocarbonyl)amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(106a) The compound2-(isopropylaminocarbonyl)amino-5-(trifluoromethyl)benzoic acid (cf.procedure (79a); 17 mg, 0.06 mmol) was incorporated into procedure(91b). Purification by RP-HPLC afforded the title compound (S)-1.5(R¹=2,4-dimethylphenyl, R³=—C(O)NHt-Bu,Z=—C(O)—R²=2-(isopropylaminocarbonyl)amino-5-(trifluoromethyl)phenyl,all other R=H; 5 mg). Exact MS calcd for C₃₀H₄₂F₃N₆O₄, the formula for(M+H)+607.3220. Found: 607.3235.

Example 107(2S)-N-tert-Butyl-2-[[[[2-(cyclohexylcarbonyl)amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(107a) 2-Amino-5-trifluorobenzoic acid (200 mg) was dissolved in THF(2.5 mL) and 2M K₂CO₃/H₂O (1 mL) prior to the addition ofcyclohexylcarbonyl chloride (0.2 mL). The solution was stirred at rt for30 min. The reaction was quenched with 1N HCl solution and extractedwith EtOAc. The organic layer was dried and concentrated (302 mg). MSfound: (2M−H)⁻=629.2.

(107b) The compound2-(cyclohexylcarbonyl)amino-5-(trifluoromethyl)benzoic acid (42 mg, 0.13mmol) was incorporated into procedure (91b). Purification by RP-HPLCafforded the title compound (S)-1.5 (R¹=2,4-dimethylphenyl,R³=—C(O)NHt-Bu, Z=—C(O)—,R²=2-(cyclohexylcarbonyl)amino-5-(trifluoromethyl)phenyl, all other R=H;3 mg). Exact MS calcd for C₃₃H₄₅F₃N₅O₄, the formula for (M+H)⁺=632.3424.Found: 632.3442.

Example 108(2S)-N-tert-Butyl-2-[[[[2-benzylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(108a) The compound 2-benzylamino-5-(trifluoromethyl)benzoic acid (cf.procedure (80a); 33 mg, 0.11 mmol) was incorporated into procedure(91b). Purification by RP-HPLC afforded the title compound (S)—1.5(R¹=2,4-dimethylphenyl, R³=—C(O)NHt-Bu,Z=—C(O)—R²=2-benzylamino-5-(trifluoromethyl)phenyl, all other R=H; 5mg). Exact MS calcd for C₃₃H₄₁F₃N₅O₃, the formula for (M+H)⁺=612.3161.Found: 612.3143.

Example 109(2S)-N-tert-Butyl-2-[[[[2-(para-chloro)benzylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(109a) The compound N-Boc 2-amino-5-(trifluoromethyl)benzoic acid (S.Takagishi, et al., Synlett 1992, 360) was transformed into its methylester as described in procedure (80a). A solution of this ester (125 mg,0.39 mmol) in DMF (6 mL) was charged with K₂CO₃ (216 mg, 1.6 mmol) andpara-chlorobenzyl bromide (160 mg, 0.78 mmol). After 1.5 h, the solutionwas diluted with EtOAc and was washed with brine solution followed by 1NHCl solution. The organic layer was then washed with Na₂CO₃ solution,water, and brine. The organic layer was dried (MgSO₄), filtered, andconcentrated. Flash chromatography of the resulting residue provided thedesired N-Boc benzylamine (69 mg), which was dissolved in THF (0.9 mL).The solution was charged with 1N LiOH (0.3 mL) and MeOH (0.3 mL). Afterstirring for 18 h, the THF was removed and the solution was made acidic(pH=5) with 1N HCl. This solution was extracted with EtOAc (2×). Theorganic layer was washed with brine, dried (Na₂SO₄), filtered, andconcentrated to give N-Boc2-(para-chlorobenzyl)amino-5-(trifluoromethyl)benzoic acid.

(109b) A solution of (S)-1.6 (l=m=0, PGN=2,4-Me₂Ph(Cbz)N, R³=CONHt-Bu,all other R=H; 55 mg, 0.12 mmol) in 1:1 methylene chloride/DMF (3 mL)was charged successively with N-Boc2-(para-chlorobenzyl)amino-5(trifluoromethyl)benzoic acid (0.15 mmol),N,N-diisopropylethylamine (0.05 mL, 0.29 mmol), and HATU (53 mg, 0.14mmol). The mixture was stirred for 12 h and diluted with EtOAc. Theorganic phase was washed with water (2×), sat. NaHCO₃, water, and brine.The organic phase was then dried (Na₂SO₄), filtered, and concentrated invacuo. The product was dissolved in 2:1 methylene chloride/TFA, stirredfor 3 h, and then concentrated in vacuo. The residue was dissolved inmethylene chloride and concentrated in vacuo; this was repeated twicemore. The resultant product was dissolved in ethanol (1 mL) and thesolution was charged with 10% Pd/C (20 mg) and cyclohexene (0.02 mL).The reaction mixture was heated at 80° C. for 30 min, cooled to RT, andfiltered. The filtrate was concentrated in vacuo. Purification byRP-HPLC afforded the title compound (S)-1.5 (R¹=2,4-dimethylphenyl,R³=—C(O)NHt-Bu, Z=—C(O)—,R²=2-(para-chloro)benzylamino-5-(trifluoromethyl)phenyl, all other R=H;6 mg). Exact MS calcd for C₃₃H₄₀Cl₁F₃N₅O₃, the formula for(M+H)⁺=646.2772. Found: 646.2782.

Example 110(2S)-N-tert-Butyl-2-[[[[2-[(beta-napthyl)methyl]amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(110a) The compound (beta-napthyl)methyl bromide (176 mg, 0.8 mmol) wasincorporated into procedure (80a) to provide2-[(beta-napthyl)methyl]amino-5-(trifluoromethyl)benzoic acid, a portion(61 mg, 0.17 mmol) of which was incorporated into procedure (91b).Purification by RP-HPLC afforded the title compound (S)-1.5(R¹=2,4-dimethylphenyl, R³=—C(O)NHt-Bu,Z=—C(O)—R²=2-((beta-napthyl)methyl)amino-5-(trifluoromethyl)phenyl, allother R=H; 3 mg). Exact MS calcd for C₃₇H₄₃F₃N₅O₃, the formula for(M+H)⁺=662.3318. Found: 662.3311.

Example 111(2S)-N-tert-Butyl-2-[[[[2-(meta-methyl)benzylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(111a) The compound meta-methylbenzyl bromide was incorporated intoprocedure (80a) to provide2-(3-methyl)benzylamino-5-(trifluoromethyl)benzoic acid, a portion (43mg, 0.14 mmol) of which was incorporated into procedure (91b).Purification by RP-HPLC afforded the title compound (S)-1.5(R¹=2,4-dimethylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=2-(meta-methyl)benzylamino-5-(trifluoromethyl)phenyl, all other R=H;5 mg). Exact MS calcd for C₃₄H₄₃F₃N₅O₃, the formula for (M+H)+626.3318.Found: 626.3288.

Example 112(2S)-N-tert-Butyl-2-[[[[2-(para-methyl)benzylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(112a) A solution of (S)-1.6 (l=m=0, PGN=2,4-Me₂Ph(Cbz)N, R³=CONHL-Bu,all other R=H; cf. procedure (91a); 164 mg, 0.35 mmol) in 1:1 methylenechloride/DMF (5 mL) was charged successively with N-Boc2-amino-5-(trifluoromethyl)benzoic acid (S. Takagishi, et al., Synlett1992, 360; 107 mg, 0.35 mmol), N,N-diisopropylethylamine (0.06 mL, 0.35mmol), and HATU (63 mg, 0.17 mmol). The mixture was stirred for 12 h anddiluted with EtOAc. The organic phase was washed with water (2×), sat.NaHCO₃, water, and brine. The organic phase was then dried (Na₂SO₄),filtered, and concentrated in vacuo to provide (S)-1.3 (l=m=0,PGN=2,4-Me₂Ph(Cbz)N, R³=CONHt-Bu, Z=—C(O)—, R²=N-Boc2-amino-5-(trifluoromethyl)phenyl, all other R=H; 249 mg). MS found:(M+H)⁺=778.5.

(112b) A solution of (S)-1.3 (l=m=0, PGN=2,4-Me₂Ph(Cbz)N, R³=CONHt-Bu,Z=—C(O)—, R²=N-Boc 2-amino-5-(trifluoromethyl)phenyl, all other R=H; cf.procedure (112a); 83 mg, 0.11 mmol) in DMF (5 mL) was charged with K₂CO₃and para-methylbenzyl bromide (41 mg, 0.22 mmol). After stirring for 1.5h, the solution was diluted with EtOAc and was washed with brinesolution followed by 1N HCl solution. The organic layer was then washedwith Na₂CO₃ solution, water, and brine. The organic layer was dried(MgSO₄), filtered, and concentrated in vacuo. The product was dissolvedin 2:1 methylene chloride/TFA (3 mL), stirred for 3 h, and thenconcentrated in vacuo. The product was dissolved in methylene chlorideand concentrated in vacuo; this was repeated twice more. The resultantproduct was dissolved in ethanol (3 mL) and the solution was chargedwith 10% Pd/C (10 mg) and cyclohexene (0.04 mL). The reaction mixturewas heated at 80° C. for 30 min, cooled to RT, and filtered. Thefiltrate was concentrated in vacuo. Purification by RP-HPLC afforded thetitle compound (S)-1.5 (R¹=2,4-dimethylphenyl, R³=—C(O)NHt-Bu,Z=—C(O)—R²=2-(para-methyl)benzylamino-5-(trifluoromethyl)phenyl, allother R=H; 5 mg). Exact MS calcd for C₃₄H₄₃F₃N₅O₃, the formula for(M+H)⁺=626.3318. Found: 626.3313.

Example 113(2S)-N-tert-Butyl-2-[[[[2-(ortho-methyl)benzylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(113a) The compound ortho-methylbenzyl bromide (0.03 mL, 0.22 mmol) wasincorporated intro procedure (112b). Purification by RP-HPLC affordedthe title compound (S)-1.5 (R¹=2,4-dimethylphenyl, R³=—C(O)NHt-Bu,Z=—C(O)—R²=2-(ortho-methyl)benzylamino-5-(trifluoromethyl)phenyl, allother R=H; 3 mg). MS found: (M+H)⁺=626.4.

Example 114(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-(para-trifluoromethyl)benzylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(114a) The compound para-(trifluoromethyl)benzyl bromide (0.03 mL, 0.22mmol) was incorporated intro procedure (112b). Purification by RP-HPLCafforded the title compound (S)-1.5 (R¹=2,4-dimethylphenyl,R³=—C(O)NHt-Bu, Z=—C(O)—,R²=2-(para-trifluoromethyl)benzylamino-5-(trifluoromethyl)phenyl, allother R=H; 5 mg). Exact MS calcd for C₃₄H₄₀F₆N₅O₃, the formula for(M+H)⁺=680.3035. Found: 680.3061.

Example 115(2S)-N-tert-Butyl-2-[[[β-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(115a) The compound 3-nitro-5-(trifluoromethyl)benzoic acid (65 mg, 0.14mmol) was incorporated into procedure (91b). Purification by RP-HPLCafforded the title compound (S)-1.5 (R¹=2,4-dimethylphenyl,R³=—C(O)NHt-Bu, Z=—C(O)—, R²=3-amino-5-(trifluoromethyl)phenyl, allother R=H; 10 mg). Exact MS calcd for C₂₆H₃₅F₃N₅O₃, the formula for(M+H)⁺=522.2692. Found: 522.2702.

Example 116(2S)-N-tert-Butyl-2-[[[[3-benzylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(116a) A solution of 3-nitro-5-(trifluoromethyl)benzoic acid (5.4 g, 23mmol) in MeOH (115 mL) was charged with 5% Pd/C, Degussa (1.09 g). Thereaction vessel was purged with hydrogen and stirred under a hydrogenatmosphere (1 atm) for 3 h. The mixture was filtered and the filtratewas concentrated in vacuo to provide 3-amino-5-(trifluoromethyl)benzoicacid (4.25 g). This material was incorporated into procedure (80a) toprovide 3-benzylamino-5-(trifluoromethyl)benzoic acid, a portion (17 mg,0.06 mmol) of which was incorporated into procedure (91b). Purificationby RP-HPLC afforded the title compound (S)-1.5 (R¹=2,4-dimethylphenyl,R³=—C(O)NHt-Bu, Z=—C(O)—, R²=3-benzylamino-5-(trifluoromethyl)phenyl,all other R=H; 3 mg). Exact MS calcd for C₃₃H₄₁F₃N₅O₃, the formula for(M+H)⁺=612.3161. Found: 612.3184.

Example 117(2S)-N-tert-Butyl-2-[[[(3-methylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(117a) Methyl3-(trifluoromethylcarbonyl)amino-5-(trifluoromethyl)benzoate (cf.procedures (116a) and (80a); 131 mg, 0.42 mmol) was dissolved in THF (5mL), and the resultant solution was charged successively with KHMDS(0.83 mL of a 0.5 M solution) and iodomethane (0.03 mL, 0.42 mL). Themixture was stirred for 16 h, quenched with sat. NaHCO₃, and extractedwith EtOAc (2×). The organic extracts were combined, washed with brine,dried (Na₂SO₄), filtered, and concentrated in vacuo. This product wasdissolved in 3:1:1 THF/MeOH/water (5 mL) and the resultant solution wascharged with lithium hydroxide (20 mg, 0.84 mmol). The reaction wasstirred for 14 h, acidified with 1N HCl, and extracted with EtOAc (2×).The organic extracts were combined, washed with water, washed withbrine, dried (Na₂SO₄), filtered, and concentrated in vacuo to provide3-methylamino-5-(trifluoromethyl)benzoic acid.

(117b) The compound 3-methylamino-5-(trifluoromethyl)benzoic acid (55mg, 0.25 mmol) was incorporated into procedure (91b). Purification byRP-HPLC afforded the title compound (S)-1.5 (R₁=2,4-dimethylphenyl,R³=—C(O)NHt-Bu, Z=—C(O)—, R²=3-methylamino-5-(trifluoromethyl)phenyl,all other R=H; 3 mg). Exact MS calcd for C₂₇H₃₇F₃N₅O₃, the formula for(M+H)⁺=536.2848. Found: 536.2857.

Example 118(2S)-N-tert-Butyl-2-[[[[3-ethylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(118a) Methyl 3-amino-5-(trifluoromethyl)benzoate (cf. procedures (116a)and (80a); 177 mg, 0.81 mmol) was dissolved in MeOH (12 mL) and theresulting solution was charged successively with acetaldehyde (0.045 mL,0.81 mmol) and sodium cyanoborohydride (64 mg, 1.01 mmol). The reactionwas stirred at RT for 12 h, concentrated in vacuo, and diluted withEtOAc. The organic phase was washed with sat. NaHCO₃, water (2×), andbrine before being dried (Na₂SO₄), filtered, and concentrated in vacuo.This product was dissolved in 3:1 THF/MeOH (12 mL) and the resultantsolution was charged with lithium hydroxide (3 mL of a 1N solution). Thereaction was stirred for 14 h, acidified with 1N HCl, and extracted withEtOAc (2×). The organic extracts were combined, washed with water,washed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuoto provide 3-ethylamino-5-(trifluoromethyl)benzoic acid.

(118b) The compound 3-ethylamino-5-(trifluoromethyl)benzoic acid (35 mg,0.15 mmol) was incorporated into procedure (91b). Purification byRP-HPLC afforded the title compound (S)-1.5 (R¹=2,4-dimethylphenyl,R³=—C(O)NHt-Bu, Z=—C(O)—, R²=3-ethylamino-5-(trifluoromethyl)phenyl, allother R=H; 10 mg). Exact MS calcd for C₂₈H₃₉F₃N₅O₃, the formula for(M+H)⁺=550.3005. Found: 550.2999.

Example 119(2S)-N-tert-Butyl-2-[[[[3-isobutylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(119a) Isobutyraldehyde (0.08 mL) was incorporated into procedure (118a)to provide 3-isobutylamino-5-(trifluoromethyl)benzoic acid (161 mg), aportion (27 mg, 0.1 mmol) of which was incorporated into procedure(91b). Purification by RP-HPLC afforded the title compound (S)-1.5(R¹=2,4-dimethylphenyl, R³=—C(O)NHt-Bu,Z=—C(O)—R²=3-isobutylamino-5-(trifluoromethyl)phenyl, all other R=H; 5mg). Exact MS calcd for C₃₀H₄₃F₃N₅O₃, the formula for (M+H)⁺=578.3318.Found: 578.3341.

Example 120

(2S)-N-tert-Butyl-2-[[[[3-propylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(120a) Propionaldehyde (0.1 mL) was incorporated into procedure (118a)to provide 3-propylamino-5-(trifluoromethyl)benzoic acid (103 mg), aportion (25 mg) of which was incorporated into procedure (91b).Purification by RP-HPLC afforded the title compound (S)-1.5(R¹=2,4-dimethylphenyl, R³=—C(O)NHt-Bu,Z=—C(O)—R²=3-propylamino-5-(trifluoromethyl)phenyl, all other R=H; 3mg). Exact MS calcd for C₂₉H₄₁F₃N₅O₃, the formula for (M+H)⁺=564.3161.Found: 564.3145.

Example 121(2S)-N-tert-Butyl-2-[[[[3-butylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(121a) Butyraldehyde (0.09 mL) was incorporated into procedure (118a) toprovide 3-butylamino-5-(trifluoromethyl)benzoic acid (172 mg), a portion(35 mg) of which was incorporated into procedure (91b). Purification byRP-HPLC afforded the title compound (S)-1.5 (R¹=2,4-dimethylphenyl,R³=—C(O)NHt-Bu, Z=—C(O)—R²=3-butylamino-5-(trifluoromethyl)phenyl, allother R=H; 5 mg). Exact MS calcd for C₃₀H₄₃F₃N₅O₃, the formula for(M+H)⁺=578.3318. Found: 578.3333.

Example 122(2S)-N-tert-Butyl-2-[[[[3-(trifluoromethylcarbonyl)amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(122a) A solution of (S)-1.5 (R¹=2,4-dimethylphenyl, R³=—C(O)NHt-Bu,Z=—C(O)—, R²=3-amino-5-(trifluoromethyl)phenyl, all other R=H; cf.procedure (115a); 14 mg, 0.03 mmol) in DMF (2 mL) was charged withpyridine (0.002 mL) and trifluoroacetic anhydride (0.004 mL). Thereaction was stirred for 12 h, diluted with water, and extracted withEtOAc. The organic phase was washed with brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. Purification by RP-HPLC affordedthe title compound (S)-1.5 (R¹=2,4-dimethylphenyl, R³=—C(O)NHL-Bu,Z=—C(O)—, R²=3-(trifluoromethylcarbonyl)amino-5-(trifluoromethyl)phenyl,all other R=H; 5 mg). MS found: (M+H)⁺=618.5.

Example 123(2S)-N-terL-Butyl-2-[[[[3-(ethoxycarbonyl)amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide

(123a) Methyl 3-amino-5-(trifluoromethyl)benzoate (cf. procedures (116a)and (80a); 236 mg, 1.01 mmol) was dissolved in THF (11 mL) and theresulting solution was charged successively with K₂CO₃ (1.6 mL of a 2.0M aq. solution) and ethylchloroformate (258 mg, 2.7 mmol). The reactionwas stirred at RT for 48 h, concentrated in vacuo, and diluted withEtOAc. The organic phase was washed with sat. NaHCO₃, water (2×), andbrine before being dried (Na₂SO₄), filtered, and concentrated in vacuo.This product was dissolved in 3:1 THF/MeOH (8 mL) and the resultantsolution was charged with lithium hydroxide (2 mL of a 1N solution). Thereaction was stirred for 14 h, acidified with 1N HCl, and extracted withEtOAc (2×). The organic extracts were combined, washed with water,washed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuoto provide 3-(ethoxycarbonyl)amino-5-(trifluoromethyl)benzoic acid. MSfound: (M−H)-=276.1.

(123b) The compound 3-(ethoxycarbonyl)amino-5-(trifluoromethyl)benzoicacid (29 mg, 0.09 mmol) was incorporated into procedure (91b).Purification by RP-HPLC afforded the title compound (S)-1.5(R₁=2,4-dimethylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=3-(ethoxycarbonyl)amino-5-(trifluoromethyl)phenyl, all other R=H; 5mg). Exact MS calcd for C₂₉H₃₉F₃N₅O₅, the formula for (M+H)⁺=594.2903.Found: 594.2917.

Example 124(2S)-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2-methyl-4-bromophenyl)methyl]amino]-propanamide

(124a) The compound 2-methyl-4-bromobenzaldehyde (M. I. Dawson, et al.,J. Med. Chem. 1984, 27, 1516-1531) was incorporated into procedure(27b). Purification by RP-HPLC afforded the title compound (S)-1.5(R¹=2-methyl-4-bromophenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=2-amino-5-(trifluoromethyl)phenyl, all other R=H, 1.5 mg). MS found:(M+H)⁺=530.0.

Example 125(2S)-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(4-bromophenyl)methyl]amino]-propanamide

(125a) The compound para-bromobenzaldehyde was incoporated intoprocedure (27b). Purification by RP-HPLC afforded the title compound(S)-1.5 (R¹=4-bromophenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=2-amino-5(trifluoromethyl)phenyl, all other R=H, 5.0 mg). MS found:(M+H)⁺=518.0.

Example 126(2S)-N-tert-Butyl-3-[[(4-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(126a) The compound para-methylbenzaldehyde (0.015 mL, 0.13 mmol) wasincorporated into procedure (1d). Purification by RP-HPLC afforded thetitle compound (S)-1.5 (R¹=4-methylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; 15 mg). Exact MS calcd forC₂₅H₃₂F₃N₄O₃, the formula for (M+H)⁺=493.2426. Found: 493.2445.

Example 127(2S)-N-tert-Butyl-3-[[(4-bromophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(127a) The compound para-bromobenzaldehyde (18 mg, 0.10 mmol) wasincorporated into procedure (1d). Purification by RP-HPLC afforded thetitle compound (S)-1.5 (R¹=4-methylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; 15 mg). MS found:(M+H)⁺=557.1.

Example 128(2S)-N-tert-Butyl-3-[[(4-bromo-2-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(128a) The compound 4-bromo-2-methylbenzaldehyde (M. I. Dawson, et al.,J. Med. Chem. 1984, 27, 1516-1531; 0.025 mL, 0.13 mmol) was incorporatedinto procedure (1d). Purification by RP-HPLC afforded the title compound(S)-1.5 (R¹=4-bromo-2-methylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; 20 mg). Exact MS calcd forC₂₅H₃₁Br₁F₃N₄O₃, the formula for (M+H)⁺=571.1532. Found: 571.1536.

Example 129(2S)-N-tert-Butyl-3-[[(4-methoxyphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(129a) The compound para-methoxybenzaldehyde (0.015 mL, 0.12 mmol) wasincorporated into procedure (1d). Purification by RP-HPLC afforded thetitle compound (S)-1.5 (R¹=4-methoxyphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; 10 mg). MS found:(M+H)⁺=509.1.

Example 130(2S)-N-tert-Butyl-3-[[(4-methoxy-2-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(130a) The compound 4-methoxy-2-methylbenzaldehyde (0.011 mL, 0.07 mmol)was incorporated into procedure (1d). Purification by RP-HPLC affordedthe title compound (S)-1.5 (R¹=4-methoxy-2-methylphenyl, R³=—C(O)NHt-Bu,Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H; 20 mg). Exact MScalcd for C₂₆H₃₄F₃N₄O₄, the formula for (M+H)⁺=523.2532. Found:523.2546.

Example 131(2S)-N-tert-Butyl-3-[[(2-methoxypyridin-5-yl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(131a) The compound 2-methoxy-5-formylpyridine (0.016 mL, 0.13 mmol) wasincorporated into procedure (1d). Purification by RP-HPLC afforded thetitle compound (S)-1.5 (R¹=2-methoxypyridin-5-yl, R³=—C(O)NHt-Bu,Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H; 29 mg). Exact MScalcd for C₂₄H₃₁F₃N₅O₄, the formula for (M+H)⁺=510.2328. Found:510.2336.

Example 132(2S)-N-tert-Butyl-3-[[(2,3-dimethyl-4-methoxy-phenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(132a) The compound 2,3-dimethyl-4-methoxy-benzaldehyde (0.025 mL, 0.13mmol) was incorporated into procedure (1d). Purification by RP-HPLCafforded the title compound (S)-1.5 (R¹=2,3-dimethyl-4-methoxyphenyl,R³=—C(O)NHt-Bu, Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H;10 mg). MS found: (M+H)⁺=537.2.

Example 133(2S)-N-tert-Butyl-3-[[(4-cyano-2-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(133a) The compound 4-cyano-2-methylbenzaldehyde (B. P. Clark, et al.,Biorg. & Med. Chem. Lett. 1997, 7, 2777-2780; 8.2 mg, 0.06 mmol) wasincorporated into procedure (1d). Purification by RP-HPLC afforded thetitle compound (S)-1.5 (R¹=4-cyano-2-methylphenyl, R³=—C(O)NHt-Bu,Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H; 7 mg). Exact MScalcd for C₂₆H₃₁F₃N₅O₃, the formula for (M+H)⁺=518.2379. Found:518.2374.

Example 134(2S)-N-tert-Butyl-3-[[(4-ethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(134a) The compound 4-ethylbenzaldehyde (0.015 mL, 0.11 mmol) wasincorporated into procedure (1d). Purification by RP-HPLC afforded thetitle compound (S)-1.5 (R¹=4-ethylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; 10 mg). Exact MS calcd forC₂₆H₃₄F₃N₄O₃, the formula for (M+H)⁺=507.2583. Found: 507.2593.

Example 135(2S)-N-tert-Butyl-3-[[(2-methyl-4-vinylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(135a) A solution of 4-bromo-2-methylbenzyl alcohol (M. I. Dawson, etal., J. Med. Chem. 1984, 27, 1516-1531; 0.81 g, 4.0 mmol) in toluene (10mL) was charged successively with Pd(PPh₃)₄ (0.13 g, 0.11 mmol), BHT(few crystals, catalytic), and vinyltributyltin (1.3 mL, 4.4 mmol). Themixture was heated at 110° C. for 3.5 h, cooled, charged with aqueous KFand stirred for 12 h at RT. The mixture was diluted with EtOAc and theresultant white precipitate was removed via filtration. The organicphase was separated, dried (Na₂SO₄), filtered, and concentrated invacuo. The residue was purified via flash chromatography to afford2-methyl-4-vinylbenzyl alcohol (0.54 g). A portion (0.27 g) of thisproduct in methylene chloride (5 mL) was added to a precooled (−78 ° C.)mixture of oxalyl chloride (1.3 mL, 2.6 mmol) and DMSO (0.3 mL, 4.3mmol) in methylene chloride (10 mL). The reactoin was charged withtriethylamine (1.0 mL, 7.2 mmol) and stirred in the cold bath for 2 h,at which point the bath was at RT. The reaction was stirred for anadditional hour at RT and then quenched with sat.

NaHCO₃. The mixture was extracted with EtOAc (2×), and the organic phasewas dried (Na₂SO₄), filtered, and concentrated in vacuo to afford pure2-methyl-4-vinylbenzaldehyde.

(135b) The compound 2-methyl-4-vinylbenzaldehyde (14 mg, 0.10 mmol) wasincorporated into procedure (1d). Purification by RP-HPLC afforded thetitle compound (S)-1.5 (R¹=2-methyl-4-vinylphenyl, R³=—C(O)NHt-Bu,Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H; 5 mg). Exact MScalcd for C₂₇H₃₄F₃N₄O₃, the formula for (M+H)⁺=519.2583. Found:519.2580.

Example 136(2S)-N-tert-Butyl-3-[[(4-ethyl-2-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(136a) The compound (S)-1.5 (R¹=2-methyl-4-vinylphenyl, R³=—C(O)NHL-Bu,Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H; cf. procedure(135b); 45 mg) was dissolved in MeOH and the solution was charged with5% Pd/C, Degussa (ca. 3 mg, catalytic). The reaction vessel was purgedwith hydrogen and then maintained under a hydrogen atmosphere (1 atmpressure) for 2 h. The mixture was diluted with MeOH, filtered, andconcentrated in vacuo. Purification by RP-HPLC afforded the titlecompound (S)-1.5 (R¹=4-ethyl-2-methylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; 7 mg). Exact MS calcd forC₂₇H₃₆F₃N₄O₃, the formula for (M+H)⁺=521.2740. Found: 521.2758.

Example 137(2S)-N-tert-Butyl-3-[[(4-isopropylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(137a) The compound 4-isopropylbenzaldehyde (0.02 mL, 0.13 mmol) wasincorporated into procedure (1d). Purification by RP-HPLC afforded thetitle compound (S)-1.5 (R¹=4-isopropylphenyl, R³=—C(O)NHL-Bu, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; 5 mg). Exact MS calcd forC₂₇H₃₆F₃N₄O₃, the formula for (M+H)⁺=521.2740. Found: 521.2759.

Example 138(2S)-N-tert-Butyl-3-[[(4-butylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(138a) The compound 4-butylbenzaldehyde (0.022 mL, 0.13 mmol) wasincorporated into procedure (1d). Purification by RP-HPLC afforded thetitle compound (S)-1.5 (R¹=4-butylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; 28 mg). Exact MS calcd forC₂₈H₃₈F₃N₄O₃, the formula for (M+H)⁺=535.2896. Found: 535.2901.

Example 139(2S)-N-tert-Butyl-3-[[(4-dimethylaminophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(139a) The compound 4-dimethylaminobenzaldehyde (11 mg, 0.07 mmol) wasincorporated into procedure (1d). Purification by RP-HPLC afforded thetitle compound (S)-1.5 (R¹=4-dimethylaminophenyl, R³=—C(O)NHt-Bu,Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H; 5 mg). Exact MScalcd for C₂₆H₃₅F₃N₅O₃, the formula for (M+H)⁺=522.2692. Found:522.2721.

Example 140(2S)-N-tert-Butyl-3-[[(4-dimethylamino-2-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(140a) The compound 4-dimethylamino-2-methylbenzaldehyde (23 mg, 0.14mmol) was incorporated into procedure (1d). Purification by RP-HPLCafforded the title compound (S)-1.5 (R¹=4-dimethylamino-2-methylphenyl,R³=—C(O)NHt-Bu, Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H;20 mg). Exact MS calcd for C₂₇H₃₇F₃N₅O₃, the formula for(M+H)⁺=536.2848. Found: 536.2833.

Example 141(2S)-N-tert-Butyl-3-[[(4-methylthiophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(141a) The compound 4-methylthiobenzaldehyde (0.05 mL, 0.37 mmol) wasincorporated into procedure (1d). Purification by RP-HPLC afforded thetitle compound (S)-1.5 (R¹=4-methylthiophenyl, R³=—C(O)NHt-Bu,Z=—C(O)—R²=3-(trifluoromethyl)phenyl, all other R=H; 3 mg). Exact MScalcd for C₂₅H₃₂F₃N₄O₃S₁, the formula for (M+H)⁺=525.2147. Found:525.2129.

Example 142(2S)-N-tert-Butyl-3-[[(4-methylsulfonylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(142a) The compound 4-methylsulfonylbenzaldehyde (13 mg, 0.07 mmol) wasincorporated into procedure (1d). Purification by RP-HPLC afforded thetitle compound (S)-1.5 (R¹=4-methylsulfonylphenyl, R³=—C(O)NHt-Bu,Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H; 7 mg). Exact MScalcd for C₂₅H₃₂F₃N₄O₅S₁, the formula for (M+H)⁺=557.2046. Found:557.2052.

Example 143(2S)-N-tert-Butyl-3-[[(4-trifluoromethoxyphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(143a) The compound 4-trifluoromethoxybenzaldehyde (0.01 mL, 0.09 mmol)was incorporated into procedure (1d). Purification by RP-HPLC affordedthe title compound (S)-1.5 (R¹=4 -trifluoromethoxyphenyl,R³=—C(O)NHt-Bu, Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H;10 mg). Exact MS calcd for C₂₅H₂₉F₆N₄O₄, the formula for(M+H)⁺=563.2093. Found: 563.2122.

Example 144(2S)-N-tert-Butyl-3-[[(3-amino-4-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(144a) The compound 4-methyl-3-nitrobenzaldehyde (28 mg, 0.17 mmol) wasincorporated into procedure (1d). The resultant product was then carriedthrough procedure (136a). Purification by RP-HPLC afforded the titlecompound (S)-1.5 (R¹=3-amino-4-methylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; 7 mg). Exact MS calcd forC₂₅H₃₃F₃N₅O₃, the formula for (M+H)⁺=508.2535. Found: 508.2541.

Example 145(2S)-N-tert-Butyl-3-[[(indol-3-yl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(145a) The compound indol-3-ylcarboxaldehyde (19 mg, 0.13 mmol) wasincorporated into procedure (1d). Purification by RP-HPLC afforded thetitle compound (S)-1.5 (R¹=indol-3-yl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; 5 mg). Exact MS calcd forC₂₆H₃₁F₃N₅O₃, the formula for (M+H)⁺=518.2379. Found: 518.2374.

Example 146(2S)-N-tert-Butyl-3-[[(2-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(146a) The compound 2-methylbenzaldehyde (0.02 mL, 0.15 mmol) wasincorporated into procedure (1d). Purification by RP-HPLC afforded thetitle compound (S)-1.5 (R¹=2-methylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; 15 mg). Exact MS calcd forC₂₅H₃₂F₃N₄O₃, the formula for (M+H)⁺=493.2426. Found: 493.2417.

Example 147(2S)-N-tert-Butyl-3-[[(2-ethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(147a) The compound 2-ethylbenzaldehyde (0.02 mL, 0.15 mmol) wasincorporated into procedure (1d). Purification by RP-HPLC afforded thetitle compound (S)-1.5 (R¹=2-ethylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; 15 mg). Exact MS calcd forC₂₆H₃₄F₃N₄O₃, the formula for (M+H)⁺=507.2583. Found: 507.2602.

Example 148(2R)-N-Ethyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(148a) Ethylamine (0.2 mL of a 2.0 M solution) and (R)-16.2(R¹=2,4-dimethylphenyl, R²=3-trifluoromethylphenyl, all other R=H; cf.procedure (6a); 36 mg) were incorporated into the above procedure (4a)to give the title amide (R)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)NHEt, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H; 10 mg). Exact MS calcd for C₂₄H₃₀F₃N₄O₃, the formula for(M+H)⁺=479.2270. Found: 479.2265.

Example 149(2R)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(149a) tert-Butylamine (0.05 mL, 0.48 mmol) and (R)-16.2(R¹=2,4-dimethylphenyl, R²=3-trifluoromethylphenyl, all other R=H; cf.procedure (6a); 36 mg) were incorporated into the above procedure (4a)to give the title amide (R)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)NHt-Bu, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H; 15 mg). Exact MS calcd for C₂₆H₃₄F₃N₄O₃, the formula for(M+H)⁺=507.2583. Found: 507.2593.

Example 150(2R)-N-[(2-methyl)hydroxyorop-2-yl]-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(150a) The compounds 2-amino-2-methylpropanol (0.08 mL, 0.79 mmol) and(R)-16.2 (R¹=2,4-dimethylphenyl, R²=3-trifluoromethylphenyl, all otherR=H; cf. procedure (6a); 60 mg) were incorporated into the aboveprocedure (4a) to give the title amide (R)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)NHCMe₂CH₂OH, Z=—C(O)—, R²=3-trifluoromethylphenyl,all other R=H; 20 mg). MS found: (M+H)⁺=523.1.

Example 151(2S)-N-tert-Amyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(151a) tert-Amylamine (70 μL) was incorporated into the above procedure(4a) to give the title amide (S)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)NHCMe₂Et, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H; 10 mg). Exact MS calcd for C₂₇H₃₆F₃N₄O₃, the formula for(M+H)⁺=521.2740. Found: 521.2736.

Example 152(2S)-N-[(2-methyl)hydroxyprop-2-yl]-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(152a) The compound 2-amino-2-methylpropanol (50 μL) was incorporatedinto the above procedure (4a) to give the title amide (S)-16.3(R¹=2,4-dimethylphenyl, —C(O)N(R^(3a))₂=—C(O)NHCMe₂CH₂OH, Z=—C(O)—,R²=3-trifluoromethylphenyl, all other R=H; 7 mg). Exact MS calcd forC₂₆H₃₄F₃N₄O₄, the formula for (M+H)⁺=523.2532. Found: 523.2537.

Example 153(2S)-N-[(1-methyl)cycloprop-1-yl]-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(153a) The compound α-methylcyclopropylamine (J. Org. Chem. 1989, 54,1815; 18 mg) was incorporated into the above procedure (4a) to give thetitle amide (S)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)NH(α-Me)c-Pr, Z=—C(O)—, R²=3-trifluoromethylphenyl,all other R=H; 7 mg). Exact MS calcd for C₂₆H₃₂F₃N₄O₃, the formula for(M+H)⁺=505.2426. Found: 505.2405.

Example 154(2S)-N-Cyclopentyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(154a) Cyclopentylamine (0.5 mL) was incorporated into the aboveprocedure (4a) to give the title amide (S)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)NHc-C₅H₉, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H; 5 mg). Exact MS calcd for C₂₇H₃₄F₃N₄O₃, the formula for(M+H)⁺=519.2583. Found: 519.2572.

Example 155(2S)-N-Cyclohexyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(155a) Cyclohexylamine (0.05 mL) was incorporated into the aboveprocedure (4a) to give the title amide (S)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)NHc-C₆H₁₁, Z=—C(O)—, R²=3-trifluoromethylphenyl,all other R=H; 10 mg). Exact MS calcd for C₂₈H₃₆F₃N₄O₃, the formula for(M+H)⁺=533.2740. Found: 533.2746.

Example 156(2S)-N-(β,β,β-Trifluoro)ethyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(156a) β,β,β-Trifluoroethylamine (0.5 mL) was incorporated into theabove procedure (4a) to give the title amide (S)-16.3(R¹=2,4-dimethylphenyl, —C(O)N(R^(3a))₂=—C(O)NHCH₂CF₃, Z=—C(O)—,R²=3-trifluoromethylphenyl, all other R=H; 5 mg). Exact MS calcd forC₂₄H₂₇F₆N₄O₃, the formula for (M+H)⁺=533.1987. Found: 533.1987.

Example 157(2S)-N-Allyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(157a) Allylamine (0.02 mL) was incorporated into the above procedure(4a) to give the title amide (S)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)NHallyl, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H; 5 mg). Exact MS calcd for C₂₅H₃₀F₃N₄O₃, the formula for(M+H)⁺=491.2270. Found: 491.2270.

Example 158(2S)-N-Cyclopropylmethyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(158a) Cyclopropylmethylamine (0.025 mL) was incorporated into the aboveprocedure (4a) to give the title amide (S)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)NHCH₂c-Pr, Z=—C(O)—, R²=3-trifluoromethylphenyl,all other R=H; 5 mg). Exact MS calcd for C₂₆H₃₂F₃N₄O₃, the formula for(M+H)⁺=505.2426. Found: 505.2440.

Example 159N-[2-[[(2S)-3-[[(2,4-dimethylphenyl)methyl]amino]-1-(pyrrolid-3-enyl)-1-oxopropyl-2-amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(159a) 3-Pyrrolidene (0.04 mL) was incorporated into the above procedure(4a) to give the title amide (S)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)c-NC₄H₆, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H; 10 mg). MS found: (M+H)⁺=503.1.

Example 160N-[2-[[(2S)-3-[[(2,4-dimethylphenyl)methyl]amino]-1-(pyrrolidinyl)-1-oxopropyl-2-amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(160a) The compound (S)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)c-NC₄H₆, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H; cf. procedure (159); 8 mg) was incorporated into procedure(136a) to give the title amide (S)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)c-NC₄H₈, Z=—C(O)—, R²=3trifluoromethylphenyl, allother R=H; 6 mg). MS found: (M+H)⁺=505.3.

Example 161N-[2-[[(2S)-3-[[(2,4-dimethylphenyl)methyl]amino]-1-(morpholinyl)-1-oxopropyl-2-amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(161a) Morpholine (0.02 mL) was incorporated into the above procedure(4a) to give the title amide (S)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)c-NC₄H₈O, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H; 5 mg). MS found: (M+H)⁺=521.3.

Example 162(2S)-N-Isobutyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(162a) Isobutylamine (0.15 mL) was incorporated into the above procedure(4a) to give the title amide (S)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)NHCH₂i-Pr, Z=—C(O)—, R²=3-trifluoromethylphenyl,all other R=H; 7 mg). Exact MS calcd for C₂₆H₃₄F₃N₄O₃, the formula for(M+H)⁺=507.2583. Found: 507.2604.

Example 163(2S)-N-sec-Butyl-3-[[(2,4-dimethyphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(163a) sec-Butylamine (0.07 mL) was incorporated into the aboveprocedure (4a) to give the title amide (S)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)NHCH(Me)Et, Z=—C(O)—, R²=3-trifluoromethylphenyl,all other R=H; 7 mg). Exact MS calcd for C₂₆H₃₄F₃N₄O₃, the formula for(M+H)⁺=507.2583. Found: 507.2554.

Example 164(2S)-N-tert-Butyl-4-[[(2,4-dimethylphenyl)methyl]amino]-3-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide

(164a) A solution of (R)-1.3 (l=m=0, PGN=N₃, R³=CH₂CO₂tBu, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; cf. procedure (31d); 388mg, 0.9 mmol) was dissolved in 3:1 methlyene chloride/TFA (12 mL) andstirred for 3 h before being concentrated in vacuo. The residue wasdissolved in methylene chloride and concentrated in vacuo; thisprocedure was repeated to provide the carboxylic acid, which was carriedthrough procedure (33a). The resultant amide (R)-1.3 (l=m=0, PGN=N₃,R³=CH₂CONHtBu, Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H,0.3 mmol) was then carried through procedure (1d). Purification byRP-HPLC provided the title compound (R)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R³=CH₂CONHL-Bu, Z=—C(O)—,R²=3-trifluoromethylphenyl, all other R=H; 10 mg). Exact MS calcd forC₂₇H₃₆F₃N₄O₃, the formula for (M+H)⁺=521.2740. Found: 521.2755.

Example 165(2S,3R)-N-Ethyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide

(165a) To a solution of N_(α)-Boc threonine (2.19 g, 10 mmol) in CH₂Cl₂(75 mL) was added BOP (4.65 g, 10.5 mmol) and ethylamine (11 mL of a 2.0M solution). The reaction was stirred for 2.5 h at room temperature andpartitioned between EtOAc and sat. NH₄Cl. The organic phase wasseparated, washed with sat. NaHCO₃ (1×), washed with brine (1×), dried(MgSO₄), filtered, and concentrated in vacuo. The residue was purifiedby flash chromatography to give (2S,3R)-5.2 (R⁶=methyl, R^(3a)=ethyl;2.22 g). MS found: (M+Na+MeCN)⁺=310.1.

(165b) The amide (2S,3R)-5.2 (R⁶=methyl, R^(3a)=ethyl; 588 mg) wasdissolved in THF, and the resultant solution was cooled to 0° C. andcharged with DEAD (511 μL, 3.23 mmol), para-nitrobenzoic acid (600 mg,3.59 mmol), and triphenylphospine (785 mg, 2.99 mmol). The reaction wasstirred at room temperature for 12 h, concentrated in vacuo, dissolvedin CH₂Cl₂, and purified by flash chromatography to give thepara-nitrobenzoate as a white solid. This material was dissolved in 25mL of 2:2:1 THF/MeOH/H₂O and treated with LiOH (192 mg of themonohydrate). The reaction was stirred at room temperature for 18 h andconcentrated in vacuo. The residue was diluted with EtOAc and washedwith 5% NaHCO₃ (1×) and brine (1×). The organic phase was dried (MgSO₄),filtered, and concentrated in vacuo to give (2S, 3S)-5.2 (R⁶=methyl,R^(3a)=ethyl; 143 mg) as a white solid. ¹H-NMR (300 MHz, CD₃OD): δ 7.94(bs, 1H), 6.57 (d, 1H), 3.98-3.92 (m, 2H), 3.27-3.18 (m, 2H), 1.44 (s,9H), 1.17 (d, 3H, J=6.3 Hz), 1.12 (t, 3H, J=7.5 Hz).

(165c) To a solution of the alcohol (2S,3S)-5.2 (R⁶=methyl,R^(3a)=ethyl; 143 mg, 0.58 mmol) in CH₂Cl₂ (10 mL) was addedN,N-diisopropylethylamine (121 μL, 0.7 mmol) and methanesulfonicanhydride (111 mg, 0.64 mmol). The reaction was stirred for 12 h at roomtemperature and partitioned between EtOAc and sat. NH₄Cl. The organicphase was washed with sat. NH₄Cl (1×), washed with brine (1×), dried(Na₂SO₄), filtered, and concentrated in vacuo to give the mesylate as anoff-yellow solid (175 mg). The mesylate was dissolved in DMSO (5 mL) andtreated with sodium azide (176 mg, 2.7 mmol). The reaction was heated at65° C. for 14 h and then partitioned between EtOAc and sat. NaHCO₃. Theorganic phase was washed with brine (1×), dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was purified via flash chromatographyto give (2S,3R)-5.3 (R⁶=methyl, R^(3a)=ethyl; 75 mg) as a white solid.MS found: (M+Na⁺ MeCN)⁺=335.2.

(165d) The carbamate (2S,3R)-5.3 (R⁶=methyl, R^(3a)=ethyl; 75 mg) wasdissolved in 2:1 CH₂Cl₂/TFA (10 mL), and the resultant mixture wasstirred at room temperature for 4 h before being concentrated in vacuo.The residue was dissolved in CH₂Cl₂, and concentrated in vacuo; thisprocedure was repeated twice more. This residue was then dissolved inbenzene and concentrated in vacuo to give the pure amine. The amine(0.276 mmol assumed) was dissolved in CH₂Cl₂ (10 mL), and the resultantsolution was charged with N,N-diisopropylethylamine (0.24 mL, 1.38mmol), 1.2 (Z=C(O)—, R²=3-trifluoromethylphenyl, all other R=H; 75 mg,0.304 mmol) and HATU (116 mg, 0.30 mmol). The reaction was stirred for72 h at room temperature and then partitioned between EtOAc and sat.NH₄Cl. The organic phase was washed with brine (1×), dried (MgSO₄),filtered, and concentrated in vacuo to give (2S,3R)-1.3 (l=m=0, PGN=N₃,R⁶=methyl, R³=—C(O)NHEt, Z=C(O)—, R²=3-trifluoromethylphenyl, all otherR=H; 175 mg). MS found: (M+Na)⁺=423.0.

(165e) The azide (2S,3R)-1.3 (l=m=0, PGN=N₃, R⁶=methyl, R³=—C(O)NHEt,Z=C(O)—, R²=3-trifluoromethylphenyl, all other R=H; 175 mg) wasdissolved in MeOH (15 mL), and the resultant solution was charged with5% Pd/C, Degussa type (125 mg), purged with hydrogen gas, and thenstirred under H₂ (1 atm) for 14 h. The mixture was filtered andconcentrated in vacuo to give the amine (2S,3R)-1.4 (l=m=0, R⁶=methyl,R³=—C(O)NHEt, Z=C(O)—, R²=3-trifluoromethylphenyl, all other R=H; 155mg). MS found: (M+H)⁺=375.2.

(165f) The amine (2S,3R)-1.4 (l=m=0, R⁶=methyl, R³=—C(O)NHEt, Z=C(O)—,R²=3-trifluoromethylphenyl, all other R=H; 78 mg, 0.14 mmol) wasdissolved in MeOH (8 mL), and the resultant solution was charged with2,4-dimethylbenzaldehyde (24 μL, 0.17 mmol), stirred for 10 min, andcharged with sodium cyanoborohydride (16 mg, 0.25 mmol). The reactionwas stirred for 12 h at room temperature and partitioned between EtOAcand sat. NaHCO₃. The aqueous phase was back-extracted with EtOAc (1×),and the organic extracts were combined, washed with brine (1×), dried(MgSO₄), filtered, and concentrated in vacuo. The residue was purifiedvia RP-HPLC to give the title compound (2S,3R)-1.5 (l=m=0,R¹=2,4-dimethylphenyl, R⁶=methyl, R³=—C(O)NHEt, Z=C(O)—,R²=3-trifluoromethylphenyl, all other R=H; 10 mg). Exact MS calcd forC₂₅H₃₂F₃N₄O₃, the formula for (M+H)+493.2427. Found: 493.2441.

Example 166(2S,3R)-N-Ethyl-3-[[(4-bromophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide

(166a) The compound para-bromobenzaldehyde (31 mg, 0.17 mmol) wasincorporated into the above procedure (165f) to give the title compound(2S,3R)-1.5 (l=m=0, R¹=4-bromophenyl, R⁶=methyl, R³=—C(O)NHEt, Z=C(O)—,R²=3-trifluoromethylphenyl, all other R=H; 10 mg). Exact MS calcd forC₂₃H₂₇Br₁F₃N₄O₃, the formula for (M+H)⁺=543.1219. Found: 543.1214.

Example 167 Methyl(2R)-2-[[(2,4-dimethylphenyl)methyl]amino]-3-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate

(167a) (R)-N_(α)-Boc,N_(β)-Cbz-diaminopropionic acid DCHA salt (R)-2.1(l=m=0; 2.0 g, 3.9 mmol) was incorporated into the above procedure (1b)to give (R)-2.2 (l=m=0; 2.32 g). MS found: (M+Na)⁺=375.1.

(167b) To a solution of (R)-2.2 (l=m=0; 2.32 g) in MeOH (40 mL) wasadded 5% Pd/C, Degussa (1.0 g). The vessel was purged with H₂, and thereaction was stirred under H₂ (1 atm) for 12 h before being filtered andconcentrated in vacuo to provide the amine, MS found: (M+H)⁺=219.3. Theamine was dissolved in 40 mL of 3:1 CH₂Cl₂/DMF and the resultingsolution was charged with N, N-diisopropylethylamine (1.4 mL), the acid1.2 (Z=—C(O)—,R²=3-trifluoromethylphenyl, all other R=H; 963 mg), andHATU (1.48 g). The reaction was stirred for 3.5 h and diluted withEtOAc. The organic phase was washed successively with sat. NH₄Cl, 5%NaHCO₃, and sat. NaCl. The organic phase was dried (Na₂SO₄), filtered,and concentrated in vacuo to provide amide (R)-23.1 (l=m=0, R⁶=CO₂Me,Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H, 2.52 g). MS found:(M+Na)⁺=470.1.

(167c) The carbamate (R)-23.1 (l=m=0, R⁶=CO₂Me, Z=—C(O)—,R²=3-trifluoromethylphenyl, all other R=H; 2.52 g) was dissolved in 3:2CH₂Cl₂/TFA (75 mL) and stirred at room temperature for 80 min beforebeing concentrated in vacuo. The residue was dissolved in CH₂Cl₂ and thesolution was concentrated in vacuo. The residue was dissolved in benzeneand the solution was concentrated in vacuo; this procedure was repeatedonce more to afford the amine as a yellow oil (3.5 g). MS found:(M+H)⁺=348.1. A portion of this amine (0.4 mmol) was dissolved in THF (6mL) and the resultant solution was charged withN,N-diisopropylethylamine (430 μL) and 2,4-dimethylbenzaldehyde (67 μL).The reaction was stirred for 15 min and charged with sodiumtriacetoxyborohydride (254 mg). The reaction was stirred for 3 h at roomtemperature and partitioned between EtOAc and sat. NaHCO₃. The organicphase was washed with brine, dried (Na₂SO₄), filtered, and concentratedin vacuo. The resultant residue was purified by reverse phase HPLC toafford the title compound (R)-1.5 (l=m=0, R¹=2,4-dimethylphenyl,R⁶=CO₂Me, Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H; 25 mg).MS found: (M+H)⁺=466.3.

Example 168(2R)-N-Ethyl-2-[[(2,4-dimethylphenyl)methyl]amino]-3-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(168a) To a solution of (R)-1.5 (l=m=0, R¹=2,4-dimethylphenyl, R⁶=CO₂Me,Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H; 19 mg) in 2:2:1THF/MeOH/H₂O (10 mL) was added LIOH (40 mg). The reaction was stirredfor 12 h at room temperature, quenched with 1 M HCl, and extracted withEtOAc (2×). The organic extracts were combined, washed with brine, dried(MgSO₄), filtered, and concentrated in vacuo to afford a white paste.This material was not characterized but rather dissolved in 3:1CH₂Cl₂/DMF (8 mL) and treated with HATU (19 mg) and ethylamine (70 μL ofa 2.0 M solution). The reaction was stirred for 3 h at room temperatureand concentrated in vacuo. The residue was purified by reverse phaseHPLC to afford the title compound (R)-1.5 (l=m=0, R¹=2,4-dimethylphenyl,R⁶=CONHEt, Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H; 5 mg).MS found: (M+H)⁺=479.4.

Example 169 Methyl(2S)-4-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanoate

(169a) (S)-N_(α)-Boc,N_(β)-Cbz-diaminobutanoic acid DCHA salt (S)-2.1(l=1, m=0; 4.93 g, 9.24 mmol) was incorporated into the above procedure(1b) to give (S)-2.2 (l=1, m=0, all R=H, 2.18 g). A portion (950 mg,2.60 mmol) of this material was incorporated into procedures (1c) &(1d). Purification by RP-HPLC provided the title compound (S)-1.5 (l=1,m=0, R¹=2,4-dimethylphenyl, R³=CO₂Me, Z=—C(O)—,R²=3-trifluoromethylphenyl, all other R=H; 10 mg). MS found:(M+H)⁺=480.3.

Example 170(2S)-4-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide

(170a) (S)-N_(α)-Fmoc, N_(γ)-Alloc-diaminobutyric acid (0.64 g, 1.0mmol), N₆₀-Fmoc glycine (0.28 g, 1.0 mmol), and3-(trifluoromethyl)benzoic acid were incorporated into the aboveprocedure (27a) to afford the resin bound (S)-21.6 (l=1, m=0,R²=3-(trifluoromethyl)phenyl, all other R=H; 700 mg).

(170b) The resin-bound (S)-21.6 (l=1, m=0, R²=3-(trifluoromethyl)phenyl,all other R=H; 210 mg) was incorporated into the above procedure (27b)to afford the title compound (S)-21.8 (l=1, m=0, R¹=2,4-dimethylphenyl,R²=3-(trifluoromethyl)phenyl, all other R=H, 4.0 mg). MS found:(M+H)⁺=465.3.

Example 171(2S)-N-Ethyl-4-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide

(171a) (S)-N_(α)-Boc,N_(γ)-Cbz-diaminobutanoic acid DCHA salt (S)-2.1(l=1, m=0; 1.03 g, 1.93 mmol) was dissolved in CH₂Cl₂ (17 mL), and theresultant solution was charged with ethylamine (5.0 mL of a 2.0 Msolution, 10 mmol) and HATU (713 mg, 1.91 mmol). The reaction wasstirred for 15 hours at room temperature, diluted with EtOAc (60 mL) andwashed with 1N HCl (2×), water (1×), and brine (1 x). The organicextracts were dried (Na₂SO₄), filtered, and concentrated in vacuo, andthe resultant residue was purified via flash chromatography to give(S)-2.3 (l=1, m=0, —C(O)N(R^(3a))₂=—C(O)NHEt; 398 mg). MS found:(M+Na)⁺=402.2.

(171b) The amide (S)-2.3 (l=1, m=0, —C(O)N(R^(3a))₂ C(O)NHEt; 398 mg)was dissolved in 2:1 CH₂Cl₂/TFA (6 mL) and stirred at room temperaturefor 3 h. The volatiles were removed in vacuo. The residue was dissolvedin CHCl₃ and concentrated in vacuo; this procedure was repeated oncemore. The residue was dissolved in EtOAc, washed with sat. NaHCO₃ (1×),water (1×), and brine (1×). The organic extracts were dried (Na₂SO₄),filtered, and concentrated in vacuo. The amine (217 mg, 0.77 mmol) wasdissolved in CH₂Cl₂ (8 mL), and the resultant solution was charged withDMF (1.5 mL), N,N-diisopropylethylamine (0.4 mL, 2.31 mmol), N_(α)-Bocglycine (142 mg, 0.81 mmol) and HATU (314 mg, 0.82 mmol). The reactionwas stirred for 15 h at room temperature, diluted with EtOAc (60 mL) andwashed with 1N HCl (2×), water (1×), sat. NaHCO₃ (1×), and brine (1×).The organic extracts were dried (Na₂SO₄), filtered, and concentrated invacuo to give (S)-1.6 (l=1, m=0, PGN=CbzHN, R³=—C(O)NHEt, all otherR=H; >quantitative mass recovery). MS found: (M+Na)⁺=459.2.

(171c) The bisamide (S)-1.6 (l=1, m=0, PGN=CbzHN, R³=—C(O)NHEt, allother R=H; assumed to be 0.77 mmol) was dissolved in 2:1 CH₂Cl₂/TFA (6mL) and stirred at room temperature for 3 h. The volatiles were removedin vacuo. The residue was dissolved in CH₂Cl₂ and concentrated in vacuo;this procedure was repeated twice more. The residue was dissolved inbenzene and concentrated in vacuo; this procedure was repeated oncemore. The product amine (assumed to be 0.77 mmol) was dissolved inCH₂Cl₂ (4 mL), and the resultant solution was charged with DMF (3 mL),N,N-diisopropylethylamine (1.6 mL, 9.2 mmol), 3-trifluoromethylbenzoicacid (371 mg, 1.95 mmol) and HATU (690 mg, 1.82 mmol). The reaction wasstirred for 15 h at room temperature, diluted with EtOAc and washed with1N HCl (2×), water (1×), sat. NaHCO₃ (1×), and brine (1×). The organicextracts were dried (Na₂SO₄), filtered, and concentrated in vacuo togive (S)-1.3 (l=1, m=0, PGN=CbzHN, R³=—C(O)NHEt, Z=—C(O)—,R²=trifluoromethylphenyl, all other R=H; 810 mg, >quantitative massrecovery). MS found: (M−H+ TFA)-=680.0.

(171d) The unpurified carbamate (S)-1.3 (l=1, m=0, PGN=CbzHN,R³=—C(O)NHEt, Z=—C(O)—, R²=trifluoromethylphenyl, all other R=H; 404 mg)was dissolved in 1:1 MeOH/THF (20 mL) and the resultant solution wascharged with 5% Pd/C (Degussa type, 350 mg). The reaction was evacuatedand then back-filled with H₂; this procedure was repeated twice more.The reaction was stirred for 12 h at room temperature and then filtered.The product was purified by RP-HPLC to give the free amine (S)-1.4 (l=1,m=0, R³=—C(O)NHEt, Z=—C(O)—, R²=trifluoromethylphenyl, all other R=H; 70mg). MS found: (M+H)⁺=375.2.

(171e) The amine (30 mg) was dissolved in MeOH (1 mL) and the resultantsolution was charged with 2,4-dimethylbenzaldehyde (13 μL) and sodiumcyanoborohydride (20 mg). The reaction was stirred at room temperaturefor 12 h, diluted with EtOAc, and washed with sat. NaHCO₃. The aqueousphase was back-extracted with EtOAc (2×), and the organic extracts werecombined, washed with brine (1×), dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was purified by RP-HPLC to give thetitle compound (S)-1.5 (l=1, m=0, R¹=2,4-dimethylphenyl, R³=—C(O)NHEt,Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H; 10 mg). Exact MScalcd for C₂₅H₃₂F₃N₄O₃, the formula for (M+H)⁺=493.2427. Found:493.2443.

Example 172(2S)-N-Ethyl-4-[[(2,4-dimethylphenyl)methyl]methylamino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide

(172a) To a cooled (0° C.) solution of (S)-1.5 (l=1, m=0,R¹=2,4-dimethylphenyl, R³=—C(O)NHEt, Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H; 6 mg) in 4:1THF/1,2-dichloroethane (1 mL) was added N,N-diisopropylethylamine (2.0μL) and formaldehyde (5 μL of a 37% aq. solution). The reaction wasstirred at room temperature for 15 min and charged with sodiumtriacetoxyborohydride (5 mg). The reaction was stirred at roomtemperature for 2 h, quenched with sat. NaHCO₃, and extracted with EtOAc(3×). The organic extracts were combined, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The residue was purified by reverse phased HPLCto afford the title compound (S)-24.1 (l=1, m=0, R¹=2,4-dimethylphenyl,R¹⁷=methyl, R³=—C(O)NHEt, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H; 3 mg). MS found: (M+H)⁺=507.4.

Example 173(2S)-N-tert-Butyl-2-[[[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-4-[[(2,4-dimethylphenyl)methyl]amino]-butanamide

(173a) tert-Butylamine (1.73 mL, 16.5 mmol) was incorporated into theabove procedure (171a) to give (S)-2.3 (l=1, m=0,—C(O)N(R^(3a))₂=—C(O)NHt-Bu; assumed 5.49 mmol). This material wascarried through procedure (171b) as described and then purified by flashchromatography to afford (S)-1.6 (l=1, m=0, PGN=CbzHN, R³=—C(O)NHt-Bu,all other R=H, 2.14 g, 4.61 mmol). MS found: (M+Na)⁺=487.

(173b) The compound (S)-1.6 (l=1, m=0, PGN=CbzHN, R³=—C(O)NHt-Bu, allother R=H; 543 g, 1.17 mmol) and N-Boc2-amino-5-(trifluoromethyl)benzoic acid (S. Takagishi, et al., Synlett1992, 360; 375 mg, 1.23 mmol) were incorporated into the above procedure(171c) to afford (S)-1.3 (l=1, m=0, PGN=CbzHN, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=N-Boc 2-amino-5-(trifluoromethyl)phenyl, all other R=H; 297 mg) afterflash chromatography. MS found: (M+Na)⁺=674.3.

(173c) The tris-amide (S)-1.3 (l=1, m=0, PGN=CbzHN, R³=—C(O)NHL-Bu,Z=—C(O)—, R²=N-Boc 2-amino-5-(trifluoromethyl)phenyl, all other R=H; 297mg) was incorporated into procedure (171d) above, but the final productwas not purified by HPLC; MS found: (M+H)⁺=518.2. This material wasimmediately subjected to the conditions outlined in procedure (171e),and the crude product thus obtained was purified by RP-HPLC to affordthe title compound (S)-1.5 (l=1, m=0, R¹=2,4-dimethylphenyl,R³=—C(O)NHt-Bu, Z=—C(O)—, R²=N-Boc 2-amino-5-trifluoromethylphenyl, allother R=H; 20 mg). Exact MS calcd for C₃₂H₄₅F₃N₅O₅, the formula for(M+H)⁺=636.3373. Found: 636.3392.

Example 174(2S)-N-tert-Butyl-2-[[[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-4-[[(2,4-dimethylphenyl)methyl]methylamino]-butanamide

(174a) The material (S)-1.5 (l=1, m=0, R¹=2,4-dimethylphenyl,R³=—C(O)NHt-Bu, Z=—C(O)—, R²=N-Boc 2-amino-5-trifluoromethylphenyl, allother R=H, 0.275 mmol) was incorporated into the above procedure (172a)to afford the title compound (S)-24.1 (l=1, m=0, R¹=2,4-dimethylphenyl,R¹⁷=methyl, R³=—C(O)NHt-Bu, Z=—C(O)—, R²=N-Boc2-amino-5-trifluoromethylphenyl, all other R=H; 20 mg) as a white powderafter RP-HPLC and lyopholization. Exact MS calcd for C₃₃H₄₇F₃N₅O₅, theformula for (M+H)⁺=650.3529. Found: 650.3516.

Example 175(2S)-N-tert-Butyl-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-4-[[(2,4-dimethylphenyl)methyl]amino]-butanamide

(175a) The compound (S)-1.5 (l=1, m=0, R¹=2,4-dimethylphenyl,R³=—C(O)NHt-Bu, Z=—C(O)—, R²=N-Boc 2-amino-5-trifluoromethylphenyl, allother R=H; 10 mg) was dissolved in 6 mL of 6:1 methylene chloride/TFAand stirred for 3 h at RT before being concentrated in vacuo. Theresidue was dissolved in methylene chloride and the solution wasconcentrated in vacuo; this procedure was repeated once more. Theresidue was purified by RP-HPLC to afford the title compound (S)-1.5(l=1, m=0, R¹=2,4-dimethylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=2-amino-5-trifluoromethylphenyl, all other R=H; 5 mg) as a whitepowder after lyopholization. Exact MS calcd for C₂₇H₃₆F₃N₅O₃, theformula for (M+H)⁺=536.2848. Found: 536.2855.

Example 176(2S)-N-tert-Butyl-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-4-[[(2,4-dimethylphenyl)methyl]methylamino]-butanamide

(176a) The compound (S)-1.5 (l=1, m=0, R¹=2,4-dimethylphenyl,R¹⁷=methyl, R³=—C(O)NHt-Bu, Z=—C(O)—R²=N-Boc2-amino-5-trifluoromethylphenyl, all other R=H; 20 mg) was incorporatedinto the above procedure (175a) to afford the title compound (S)-24.1(l=1, m=0, R¹=2,4-dimethylphenyl, R¹⁷=methyl, R³=—C(O)NHL-Bu, Z=—C(O)—,R²=2-amino-5-trifluoromethylphenyl, all other R=H; 10 mg) as a whitepowder after RP-HPLC and lyopholization. Exact MS calcd forC₂₈H₃₈F₃N₅O₃, the formula for (M+H)⁺=550.3005. Found: 550.3003.

Example 177(2S)-N-tert-Butyl-2-[[[β-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-4-[[(2,4-dimethylphenyl)methyl]amino]-butanamide

(177a) The compound (S)-1.6 (l=1, m=0, PGN=CbzHN, R³=—C(O)NHt-Bu, allother R=H, 0.61 mmol) and 3-nitro-5-(trifluoromethyl)benzoic acid (143mg, 0.61 mmol) were incorporated into the above procedure (171c) toafford (S)-1.3 (l=1, m=0, PGN=CbzHN, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=3-amino-5-(trifluoromethyl)phenyl, all other R=H; 279 mg) after flashchromatography.

(177b) The tris-amide (S)-1.3 (l=1, m=0, PGN=CbzHN, R³=—C(O)NHt-Bu,Z=—C(O)—, R²=3-amino-5-(trifluoromethyl)phenyl, all other R=H; 279 mg)was incorporated into procedure (171d) above, but the final product wasnot purified by HPLC; MS found: (M+H)⁺=418.2. Half of this material(estimated 0.24 mmol) was immediately subjected to the conditionsoutlined in procedure (171e), and the crude product thus obtained waspurified by RP-HPLC to afford the title compound (S)-1.5 (l=1, m=0,R¹=2,4-dimethylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=3-amino-5-trifluoromethylphenyl, all other R=H; 20 mg). Exact MScalcd for C₂₇H₃₇F₃N₅O₃, the formula for (M+H)⁺=536.2848. Found:536.2852.

Example 178(2S)-N-tert-Butyl-2-[[[[3-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-4-[[(4-ethylphenyl)methyl]amino]-butanamide

(178a) The tris-amide (S)-1.3 (l=1, m=0, PGN=CbzHN, R³=—C(O)NHt-Bu,Z=—C(O)—, R²=3-amino-5-(trifluoromethyl)phenyl, all other R=H; 279 mg)was incorporated into procedure (171d) above, but the final product wasnot purified by HPLC; MS found: (M+H)⁺=418.2. Half of this material(estimated 0.24 mmol) was immediately subjected to the conditionsoutlined in procedure (171e), substituting 4-ethylbenzaldehyde (0.033mL, 0.24 mmol) for 2,4-dimethylbenzaldehyde. The crude product thusobtained was purified by RP-HPLC to afford the title compound (S)-1.5(l=1, m=0, R¹=4-ethylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=3-amino-5-trifluoromethylphenyl, all other R=H; 15 mg). Exact MScalcd for C₂₇H₃₇F₃N₅O₃, the formula for (M+H)⁺=536.2848. Found:536.2843.

Example 179(2S)-N-tert-Butyl-4-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide

(179a) The compound (S)-1.6 (l=1, m=0, PGN=CbzHN, R³=—C(O)NHt-Bu, allother R=H, 2.42 mmol) and 3-(trifluoromethyl)benzoic acid (460 mg, 2.42mmol) were incorporated into the above procedure (171c) to afford(S)-1.3 (l=1, m=0, PGN=CbzHN, R³=—C(O)NHt-Bu, Z=—C(O)—,R²=3-(trifluoromethyl)phenyl, all other R=H; 1.07 mg) after flashchromatography. MS found: (M+Na)⁺=559.2.

(179b) The tris-amide (S)-1.3 (l=1, m=0, PGN=CbzHN, R³=—C(O)NHt-Bu,Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H, 1.43 mmol) wasincorporated into procedure (171d) above, but the final product was notpurified by HPLC. Half of this material (estimated 0.70 mmol) wasimmediately subjected to the conditions outlined in procedure (171e),and the crude product thus obtained was purified by RP-HPLC to affordthe title compound (S)-1.5 (l=1, m=0, R¹=2,4-dimethylphenyl,R³=—C(O)NHt-Bu, Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H; 10mg). Exact MS calcd for C₂₇H₃₆F₃N₄O₃, the formula for (M+H)⁺=521.2740.Found: 521.2739.

Example 180(2S)-N-tert-Butyl-4-[[(4-ethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide

(180a) The tris-amide (S)-1.3 (l=1, m=0, PGN=CbzHN, R³=—C(O)NHt-Bu,Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H, 1.43 mmol) wasincorporated into procedure (171d) above, but the final product was notpurified by HPLC. Half of this material (estimated 0.70 mmol) wasimmediately subjected to the conditions outlined in procedure (171e),substituting 4-ethylbenzaldehyde (0.096 mL, 0.7 mmol) for2,4-dimethylbenzaldehyde. The crude product thus obtained was purifiedby RP-HPLC to afford the title compound (S)-1.5 (l=1, m=0,R¹=4-ethylphenyl, R³=—C(O)NHt-Bu, Z=—C(O)—, R²=3-trifluoromethylphenyl,all other R=H; 9 mg). Exact MS calcd for C₂₇H₃₆F₃N₄O₃, the formula for(M+H)⁺=521.2740. Found: 521.2741.

Example 181(2S)-N-Ethyl-5-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-pentanamide

(181a) (S)-N_(α)-Boc,N_(δ)-Cbz-ornithine (S)-2.1 (l=m=1; 1.56 g, 4.23mmol) was incorporated into the above procedure (171a) to give (S)-2.3(l=m=1, —C(O)N(R^(3a))₂=—C(O)NHEt; 1.02 g). MS found: (M+Na)⁺=416.2.This material was carried through procedures (171b)-(171e) to give thetitle compound (S)-1.5 (l=m=1, R¹=2,4-dimethylphenyl, R³=—C(O)NHEt,Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H; 15 mg). Exact MScalcd for C₂₆H₃₄F₃N₄O₃, the formula for (M+H)⁺=507.2583. Found:507.2599.

Example 182N-[2-[[(1S,2S/R)-1-[[[(2,4-dimethylphenyl)methyl]methylamino]methyl]-2-hydroxy-3-(methyl)butyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(182a) The compound (1S,2S/R)-1.5 (l=m=0, R¹=2,4-dimethylphenyl,R³=—CH(OH)i-Pr, Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H;31 mg, 0.05 mmol) was incorporated into procedure (172a) above. Theresidue was purified by RP-HPLC to separate starting material and thetitle compound (1S,2S/R)-24.1 (l=m=0, R¹=2,4-dimethylphenyl, R¹⁷=Me,R³=—CH(OH)i-Pr, Z=—C(O)—, R²=3-(trifluoromethyl)phenyl, all other R=H; 5mg), which was obtained as white powder after lyopholization. Exact MScalcd for C₂₆H₃₅F₃N₃O₃, the formula for (M+H)⁺=494.2631. Found:494.2643.

Example 183N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]methylamino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(isopropylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide

(183a) The compound (1S,2S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl,R³=—CH(OH)n-propyl, Z=—C(O)—,R²=2-(isopropylaminocarbonyl)amino-5-(trifluoromethyl)phenyl, all otherR=H; cf. procedure (65a); 23 mg, 0.043 mmol) was dissolved in MeOH (0.5mL), and the solution was charged with formaldehyde (37% aq. solution,0.003 mL, 0.043 mmol) and acetic acid (0.005 mL). The reaction wasstirred for 15 min at RT and then charged with sodium cyanoborohydride(3.4 mg, 0.054 mmol). The reaction was stirred for 48 h at RT and thenpartitioned between EtOAc and sat. NaHCO₃. The organic phase was washedwith brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Theresidue was purified by RP-HPLC to provide the title compound (S)-24.1(l=1, m=0, R¹=2,4-dimethylphenyl, R¹⁷=methyl, R³=—CH(OH)n-Pr, Z=—C(O)—,R²=2-(isopropylaminocarbonyl)amino-5-trifluoromethylphenyl, all otherR=H; 3 mg). Exact MS calcd for C₃₀H₄₃F₃N₅O₄, the formula for(M+H)⁺=594.3267. Found: 594.3276.

Example 184N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]isopropylamino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(isopropylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide

(184a) The compound (1S,2S)-1.5 (l=m=0, R¹=2,4-dimethylphenyl,R³=—CH(OH)n-propyl, Z=—C(O)—,R²=2-(isopropylaminocarbonyl)amino-5-(trifluoromethyl)phenyl, all otherR=H; cf. procedure (65a); 25 mg, 0.043 mmol) was combined with acetone(0.003 mL, 0.043 mmol) in procedure (183a). The product was purified byRP-HPLC to provide the title compound (S)-24.1 (l=1, m=0,R¹=2,4-dimethylphenyl, R¹⁷=isopropyl, R³=—CH(OH)n-Pr, Z=—C(O)—,R²=2-(isopropylaminocarbonyl)amino-5-trifluoromethylphenyl, all otherR=H; 3 mg). Exact MS calcd for C₃₂H₄₇F₃N₅O₄, the formula for(M+H)⁺622.3580. Found: 622.3588.

Example 185N-[2-[[(1S,2S)-1-[[[(4-ethylphenyl)methyl]methylamino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(isopropylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide

(185a) The compound (1S,2S)-1.5 (l=m=0, R¹=4-ethylphenyl,R³=—CH(OH)n-propyl, Z=—C(O)—,R²=2-(isopropylaminocarbonyl)amino-5-(trifluoromethyl)phenyl, all otherR=H; cf. procedure (74a); 25 mg, 0.043 mmol) was incorporated intoprocedure (183a). Purification by RP-HPLC provided the title compound(S)-24.1 (l=1, m=0, R¹=4-ethylphenyl, R¹⁷=Me, R³=—CH(OH)n-Pr, Z=—C(O)—,R²=2-(isopropylaminocarbonyl)amino-5-trifluoromethylphenyl, all otherR=H; 3 mg). Exact MS calcd for C₃₀H₄₃F₃N₅O₄₁ the formula for(M+H)⁺=594.3267. Found: 594.3273.

Example 186N-[2-[[(1S,2S)-1-[[[(4-ethylphenyl)methyl]isopropylamino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(isopropylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide

(186a) The compound (1S,2S)-1.5 (l=m=0, R¹=4-ethylphenyl,R³=—CH(OH)n-propyl, Z=—C(O)—,R²=2-(isopropylaminocarbonyl)amino-5-(trifluoromethyl)phenyl, all otherR=H; cf. procedure (74a); 23 mg, 0.041 mmol) was combined with acetone(0.003 mL, 0.041 mmol) and incorporated into procedure (183a).Purification by RP-HPLC provided the title compound (S)-24.1 (l=1, m=0,R¹=4-ethylphenyl, R¹⁷=isopropyl, R³=—CH(OH)n-Pr, Z=—C(O)—,R²=2-(isopropylaminocarbonyl)amino-5-trifluoromethylphenyl, all otherR=H; 3 mg). Exact MS calcd for C₃₂H₄₇F₃N₅O₄, the formula for(M+H)⁺=622.3592. Found: 622.3588.

Example 187(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]methylamino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide

(187a) The compound (S)-16.3 (R¹=2,4-dimethylphenyl,—C(O)N(R^(3a))₂=—C(O)NHt-Bu, Z=—C(O)—, R²=3-trifluoromethylphenyl, allother R=H; cf. procedure (10a); 11 mg, 0.02 mmol) was carried throughprocedure (172a). The product was purified by RP-HPLC to afford thetitle compound (S)-24.1 (l=m=0, R¹=2,4-dimethylphenyl, R¹⁷=methyl,R³=—C(O)NHL-Bu, Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H; 6mg). MS found: (M+H)⁺=521.2.

Example 188N-[2-[[1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(188a) A solution of 1-amino-1-cyanocyclohexane (T. A. Keating and R. W.Armstrong, J. Am. Chem. Soc. 1996, 118, 2574; 0.55 g, 4.4 mmol) in DMF(15 mL) was charged sequentially with the acid 1.2 (all R=H,Y=3-trifluoromethylphenyl; 1.09 g, 4.4 mmol), BOP (2.15 g, 4.9 mmol),and N,N-diisopropylethylamine (1.9 mL, 11.1 mmol). The reaction wasstirred for 12 h at room temperature and partitioned between EtOAc andbrine. The organic phase was dried (Na₂SO₄), filtered, and concentratedin vacuo. The resultant residue was purified by flash chromatography toafford the productN-[2-[(1-cyanocyclohexyl)amino]-2-oxoethyl]-3(trifluoromethyl)benzamide(300 mg). MS found: (M+Na)⁺=376.2.

(188b) A solution ofN-[2-[(1-cyanocyclohexyl)amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide(300 mg) in 7:2 MeOH/CHCl₃ (9 mL) was charged with 5% Pd/C, Degussa (100mg) and transferred to a Parr vessel. The reaction was shaken under 50psi of H₂ for 12 h, charged with another 100 mg of Pd catalyst, andshaken for another 5 h at 50 psi of H₂. The reaction mixture wasfiltered and concentrated in vacuo to afford the crude amine 1.4 (l=m=0,(R³, R¹²)=—(CH₂)₄—, Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H;120 mg). MS found: (M+H)⁺=358.2.

(188c) A solution of the amine 1.4 (l=m=0, (R³, R¹²)=—(CH₂)₄—, Z=—C(O)—,R²=3-trifluoromethylphenyl, all other R=H; 57 mg, 0.15 mmol) in THF (4mL) was charged with N,N-diisopropylethylamine (0.12 mL, 0.72 mmol),2,4-dimethylbenzaldehyde (22 mg, 0.15 mmol), 4 Å molecular sieves(powdered, 60 mg), and glacial acetic acid (8 mL, 0.15 mmol). Thereaction was stirred at room temperature for 3 h, charged with sodiumtriacetoxyborohydride (46 mg, 0.22 mmol), stirred for another 1 h atroom temperature, and filtered. The filtrate was partitioned betweenEtOAc and sat. NaHCO₃, and the organic phase was concentrated in vacuo.The residue was purified by reverse phase HPLC to give the titlecompound 1.5 (l=m=0, R¹=2,4-dimethylphenyl, (R³, R¹²)=—(CH₂)₄—,Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H, 8.0 mg). MS found:(M+H)⁺=476.4.

Example 189N-[2-[[1-[[[(4-chlorophenyl)methyl]amino]methyl]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(189a) para-Chlorobenzaldehyde (14 mg) was incorporated into the aboveprocedure (188c) to give the title compound 1.5 (l=m=0,R¹=4-chlorophenyl, (R³, R¹²) —(CH₂)₄—, Z=—C(O)—,R²=3-trifluoromethylphenyl, all other R=H, 7.0 mg). MS found:(M+H)⁺=482.2.

Example 190N-[2-[[1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide

(190a) To a solution of 1-[1,1-(dimethyl)ethoxycarbonyl]aminocyclopentylcarboxaldehyde (D. Braghiroli and M. Di Bella, Tetrahedron Lett. 1996,37, 7319; 1.10 g, 5.16 mmol) in trimethyl orthoformate (20 mL) was added2,4-dimethylbenzylamine (1.4 g) and the reaction mixture stirred at roomtemperature for 8 h. Sodium cyanoborohydride (0.96 g) and methanol (2.5mL)-were added consecutively and the suspension stirred at roomtemperature for 12 h. The mixture was quenched with water and extractedwith dichloromethane (2×). The organic extracts were washed with brine,dried (Na₂SO₄), and concentrated in vacuo. Purification by flashchromatography (SiO₂) provided N-Boc1-[[(2,4-dimethylphenyl)methyl]amino]methylcyclopentylamine (974 mg,57%) MS found: (M+H)⁺=333. To a solution of this amine (500 mg, 1.63mmol) and triethylamine (0.5 mL, 3.58 mmol) in CH₂Cl₂ (50 mL) was addedbenzyl chloroformate (512 μL, 3.58 mmol) and the reaction mixturestirred at room temperature for 20 h. The mixture was washedconsecutively with water (10 mL), saturated aqueous NaHCO₃ (10 mL), andbrine (20 mL), dried over magnesium sulfate/sodium sulfate, andconcentrated in vacuo to give the product carbamate 1.1 (l=m=0,PGN=2,4-Me₂Ph(Cbz)N, R³, R¹²=c-C₄H₈, all other R=H, 599 mg) as a yellowoil. ¹H NMR (300 MHz, CDCl₃) δ 7.45-7.38 (m, 5H), 7.20-7.05 (m, 2H),7.00-6.85 (m, 3H), 5.06 (s, 2H), 4.52 (s, 2H), 3.63 (s, 2H), 2.30 (s,6H), 1.95-1.50 (m, 8H), 1.38 (s, 9H).

(190b) The carmbamate 1.1 (l=m=0, PGN=2,4-Me₂Ph(Cbz)N, R³, R¹²=c-C₄H₈,all other R=H, 0.68 mmol) was incorporated into procedure (1c). Theproduct (70 mg, 0.10 mmol) was dissolved in pyridine (0.2 mL) andmethanol, and the solution was charged with 10% Pd/C (50 mg). Thereaction mixture was stirred vigorously under an atmosphere of H₂(g) atroom temperature for 1 h. The mixture was filtered through a pad ofdiatomaceous earth and the filtrate concentrated in vacuo. The residuewas dissolved in CH₂Cl₂ (20 mL) at 0° C., then trifluoroacetic acid wasadded and the mixture stirred for 5 min at 0° C. Purification by RP-HPLCprovided the title compound 1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³,R¹²=c-C₄H₈, Z=—C(O)—, R²=3-trifluoromethylphenyl, all other R=H; 77 mg).MS found: (M+H)⁺=462.

Example 191N-[2-[[1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]cyclopentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide

(191a) The carmbamate 1.1 (l=m=0, PGN=2,4-Me₂Ph(Cbz)N, R³,R¹²=c-C₄H₈,all other R=H, 270 mg, 0.74 mmol) was combined with 1.2 (Z=—C(O)—,R²=N-Boc 2-amino-5-(trifluoromethyl)benzoic acid, all other R=H; 0.74mmol) and incorporated into procedure (1c). The product (60 mg, 0.08mmol) was dissolved in pyridine (0.2 mL) and methanol, and the solutionwas charged with 10% Pd/C (50 mg). The reaction mixture was stirredvigorously under an atmosphere of H₂ (g) at room temperature for 1 h.The mixture was filtered through a pad of diatomaceous earth and thefiltrate concentrated in vacuo. The residue was dissolved in CH₂Cl₂ (20mL) at 0° C., then trifluoroacetic acid was added and the mixturestirred for 5 min at 0° C. Purification by RP-HPLC provided the titlecompound 1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³,R¹²=c-C₄H₈, Z=—C(O)—,R²=N-Boc 2-amino-5-trifluoromethylphenyl, all other R=H; 36 mg). MSfound: (M+H)⁺=577.

Example 192N-[2-[[1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]cyclopropyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide

(192a) 1-[1,1-(Dimethyl)ethoxycarbonyl]aminocyclopropyl carboxaldehyde(D. Braghiroli and M. Di Bella, Tetrahedron Lett. 1996, 37, 7319; 3.6 g,19.4 mmol) was incorporated into procedure (190a) to provide thecarbamate X (949 mg), which was incorporated into procedure (191a).Purification by RP-HPLC provided the title compound 1.5 (l=m=0,R¹=2,4-dimethylphenyl, R³,R¹²=c-C₂H₄, Z=—C(O)—, R²=N-Boc2-amino-5-trifluoromethylphenyl, all other R=H; 43 mg). MS found:(M+H)⁺=549.

Example 193N-[2-[[1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]cyclopropyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide

(193a) The compound 1.5 (l=m=0, R¹=2,4-dimethylphenyl, R³,R¹²=c-C₂H₄,Z=—C(O)—, R²=N-Boc 2-amino-5-trifluoromethylphenyl, all other R=H; 15mg) was carried through procedure (48a). Purification by RP-HPLCprovided the title compound 1.5 (l=m=0, R¹-2,4-dimethylphenyl,R³,R¹²=c-C₂H₄, Z=—C(O)—, R²=2-amino-5-trifluoromethylphenyl, all otherR=H; 13 mg). MS found: (M+H)⁺=449.

Example 194(2S)-N-Ethyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-2-methyl-propanamide

(194a) A solution of racemic alpha-methylserine (2.33 g) was dissolvedin 1:1 THF/water (160 mL) and charged successively with triethylamine(3.0 mL) and dibenzyldicarbonate (6.0 g). The reaction was stirred for48 h at RT, quenched with 50 mL of 1 N NaOH, and extracted with Et₂O(2×50 mL). The aqueous phase was acidified with 1N HCl (solution pH now<2) and extracted with EtOAc (3×100 mL). The organic extracts werecombined, washed with brine, dried (Na₂SO₄), filtered, and concentratedin vacuo to afford the carbamate as a colorless oil (2.93 g). Theentirity of the carbamate was dissolved in methylene chloride (100 mL)and the solution was charged with HATU (3.99 g), ethylamine (19 mL of a2.0 M solution), and DMAP (117 mg). The reaction was stirred at RT for16 h and partitioned between EtOAc and sat. NH₄Cl. The organic phase waswashed with sat. NaHCO₃, brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. Flash chromatography providedrac-N-ethyl-2-(benzyloxycarbonyl)amino-3-hydroxy-2-methyl-propanamide(900 mg). MS found: (M+Na)⁺=303.

(194b) A solution ofrac-N-ethyl-2-(benzyloxycarbonyl)amino-3-hydroxy-2-methyl-propanamide(900 mg) in methylene chloride (40 mL) was charged with pyridine (1.3mL) and Dess-Martin periodinane (1.36 g). The reaction was stirred at RTfor 16 h and then partitioned between EtOAc and sat. NaHCO₃. The organicphase was washed with successively with sat. Na₂S₂O₃ and brine, and thendried (Na₂SO₄), filtered, and concentrated in vacuo to provide thealdehyde. The aldehyde (assumed 3.2 mmol) was dissolved in THF (30 mL)and the solution was charged with 2,4-dimethylbenzylamine (0.45 mL),acetic acid (0.55 mL), and sodium triacetoxyborohydride (2.0 g). Thereaction was stirred for 16 h at RT and then partitioned between EtOAcand sat. NaHCO₃. The aqueous phase was extracted with EtOAc (2×), andthe combined organic extracts were washed with brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. Flash chromatography provided theamine as a yellow oil (785 mg), which was dissolved in 1:1 THF/water (20mL) and then treated with triethylamine (0.275 mL) anddi-(tert-butyl)dicarbonate. The mixture was stirred at RT for 16 h andthen partitioned between EtOAc and sat. NH₄Cl. The organic phase waswashed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuo.residue was purified via flash chromatography (SiO₂) to afford thebiscarbamate as a colorless oil (650 mg). The product was dissolved inMeOH (13 mL) and the resultant solution was charged with Pd/BaSO₄ (350mg). The vessel was purged with hydrogen and stirred under an atmosphereof hydrogen for 2 h before being filtered. The filtrate was concentratedin vacuo to afford the primary amine as a colorless oil. MS found:(M+H)⁺=364.5.

(194c) The primary amine (1.4 mmol) from procedure (194b) was dissolvedin methylene chloride (15 mL) and the resultant solution was chargedwith N-Cbz glycine (300 mg), HATU (600 mg), andN,N-diisopropylethylamine (0.58 mL). The reaction was stirred at RT for16 h and partitioned between EtOAc and sat. NH₄Cl. The organic phase waswashed with sat. NaHCO₃, brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. A portion (525 mg, 0.95 mmol) of the product wasdissolved in MeOH (10 mL) and the resultant solution was charged with 5%Pd/C (150 mg). The vessel was purged with hydrogen and stirred under anatmosphere of hydrogen for 1.5 h before being filtered. The filtrate wasconcentrated in vacuo to afford the primary amine as a colorless oil. MSfound: (M+H)⁺=421.4.

(194d) The primary amine (0.95 mmol) from procedure (194c) was dissolvedin methylene chloride (10 mL) and the resultant solution was chargedwith N-Boc-2-amino-5-(trifluoromethyl)benzoic acid (S. Takagishi, etal., Synlett 1992, 360; 290 mg), HATU (361 mg), andN,N-diisopropylethylamine (0.50 mL). The reaction was stirred at RT for16 h and partitioned between EtOAc and sat. NH₄Cl. The organic phase waswashed with sat. NaHCO₃, brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The product was dissolved in 2:1 methylenechloride/TFA (12 mL) and stirred at RT for 2.5 h. The reaction wasconcentrated in vacuo; the residue was dissolved in benzene andconcentrated in vacuo. Purification by RP-HPLC afforded the titlecompound rac-1.5 (R¹=2,4-dimethylphenyl, R³=—C(O)NHEt, R¹²=Me, Z=—C(O)—,R²=2-amino-5-trifluoromethylphenyl, all other R=H; 30 mg). Exact MScalcd for C₂₅H₃₃F₃N₅O₃, the formula for (M+H)⁺=508.2535. Found:508.2537.

Table of Examples

The following tables illustrate examples of the present invention. Thedata in the “MS” columns represent the values observed for the (M+H)⁺ions in electrospray mass spectroscopy experiments; “NMR” indicates that¹H-NMR spectroscopy was used in lieu of mass spectroscopy forcharacterization purposes. The substituents listed in each table are tobe paired with the structure embedded in the table heading. Thesynthesis of all of these compounds has been described in detail in theprevious section (Examples). TABLE 1 examples 1-164 No. R¹ R¹⁶ * R³ R²MS 1

H (S)

466 2

H (R)

466 3

H (S)

452 4

H (S)

465 5

H (S)

451 6

H (R)

451 7

H (S)

479 8

H (S)

541 9

H (S)

493 10

H (S)

507 11

H (S)

491 12

H (S)

505 13

H (S)

527 14

H (S)

479 15

H (S)

495 16

H (S)

472 17

H (S)

457 18

H (S)

485 19

Me (S)

486 20

Me (S)

480 21

H (S)

NMR 22

H (S)

462 23

H (S)

482 24

H (S)

516 25

H (S)

581 26

H (S)

481 27

H (S)

466 28

H (S)

438 29

H (R)

438 30

H (S)

452 31

H (R)

522 32

H (R)

498 33

H (S)

622 34

H (S)

522 35

H (S)

686 36

H (S)

586 37

H (S)

480 38

H (S)

480 39

H (S)

514 40

H (S)

514 41

H (S)

528 42

H (S)

528 43

H (S)

494 44

H (S)

494 45

H (S)

466 46

H (S)

466 47

H (S)

581 48

H (S)

481 49

H (S)

609 50

H (S)

609 51

H (S)

509 52

H (S)

509 53

H (S)

508 54

H (S)

508 55

H (S)

480 56

H (S)

480 57

H (S)

595 58

H (S)

595 59

H (S)

495 60

H (S)

495 61

H (S)

495 62

H (S)

495 63

H (S)

566 64

H (S)

566 65

H (S)

580 66

H (S)

580 67

H (S)

592 68

H (S)

578 69

H (S)

552 70

H (S)

608 71

H (S)

607 72

H (S)

595 73

H (S)

495 74

H (S)

580 75

H (S)

608.5 76

H (S)

624.5 77

H (S)

524 78

H (S)

551 79

H (S)

537 80

H (S)

585.6 81

H (S)

609 82

H (S)

509 83

H (S)

581 84

H (S)

481 85

H (S)

609 86

H (S)

509 87

H (S)

637.6 88

H (S)

537 89

H (S)

607.5 90

H (S)

507 91

H (S)

523 92

H (S)

489 93

H (S)

539 94

H (S)

557 95

H (S)

538 96

H (S)

468 97

H (S)

550 98

H (S)

564 99

H (S)

578 100

H (S)

578 101

H (S)

604 102

H (S)

564 103

H (S)

578 104

H (S)

579

H (S)

608 106

H (S)

607 107

H (S)

632 108

H (S)

612 109

H (S)

646 110

H (S)

662 111

H (S)

626 112

H (S)

626 113

H (S)

626 114

H (S)

680 115

H (S)

522 116

H (S)

612 117

H (S)

536 118

H (S)

550 119

H (S)

578 120

H (S)

564 121

H (S)

578 122

H (S)

618.5 123

H (S)

594 124

H (S)

530 125

H (S)

518 126

H (S)

493 127

H (S)

557 128

H (S)

571 129

H (S)

509 130

H (S)

523 131

H (S)

510 132

H (S)

537 133

H (S)

518 134

H (S)

507 135

H (S)

519 136

H (S)

521 137

H (S)

521 138

H (S)

535 139

H (S)

522 140

H (S)

536 141

H (S)

525 142

H (S)

557 143

H (S)

563 144

H (S)

508 145

H (S)

518 146

H (S)

493 147

H (S)

507 148

H (R)

479 149

H (R)

507 150

H (R)

523 151

H (S)

521 152

H (S)

523 153

H (S)

505 154

H (S)

519 155

H (S)

533 156

H (S)

533 157

H (S)

491 158

H (S)

505 159

H (S)

503 160

H (S)

505 161

H (S)

521 162

H (S)

507 163

H (S)

507 164

H (R)

521

TABLE 2

examples 165-168 No. R¹ * R⁶ R³ R² MS 165

(R) Me

493 166

(R) Me

543 167

(R)

H

466 168

(R)

H

479

TABLE 3

examples 169-187 No. R¹ R¹⁷ m R³ R² MS 169

H 1

480 170

H 1

465 171

H 1

493 172

Me 1

507 173

H 1

636 174

Me 1

650 175

H 1

536 176

Me 1

550 177

H 1

536 178

H 1

536 179

H 1

521 180

H 1

521 181

H 2

507 182

Me 0

494 183

Me 0

594 184

i-Pr 0

622 185

Me 0

594 186

i-Pr 0

622 187

Me 0

521

TABLE 4

examples 188-194 No. R¹ R¹⁶ R¹⁷ G R² MS 188

H H

476 189

H H

482 190

H H

462 191

H H

577 192

H H

549 193

H H

449 194

H H

508

Utility

Compounds of formula I are shown to be modulators of chemokine andchemokine receptor activity using assays known by those skilled in theart. In this section, we describe these assays and give their literaturereference. By displaying activity in these assays of MCP-1 antagonism,compounds of formula I are expected to be useful in the treatment ofhuman diseases associated with chemokines and their cognate receptors.

Antagonism of MCP-1 Binding to Human PBMC

-   (Yoshimura et al., J. Immunol. 1990, 145, 292)

All examples of the present invention have activity in the antagonism ofMCP-1 binding to human PBMC (human peripheral blood mononuclear cells)described here. The definition of activity in this assay is a compounddemonstrating 50% inhibition of MCP-1 binding (IC₅₀) at a concentrationof 20 μM or lower.

Millipore filter plates (#MABVN1250) are treated with 100 μl of bindingbuffer (0.5% bovine serum albumin, 20 mM HEPES buffer and 5 mM magnesiumchloride in RPMI 1640 media) for thirty minutes at room temperature. Tomeasure binding, 50 μl of binding buffer, with or without a knownconcentration compound, is combined with 50 μl of ¹²⁵-I labeled humanMCP-1 (to give a final concentration of 150 pM radioligand) and 50 μl ofbinding buffer containing 5×10⁵ cells. Cells used for such bindingassays can include human peripheral blood mononuclear cells isolated byFicoll-Hypaque gradient centrifugation, human monocytes (Weiner et al.,J. Immunol. Methods. 1980, 36, 89), or the THP-1 cell line whichexpresses the endogenous receptor. The mixture of compound, cells andradioligand are incubated at room temperature for thirty minutes. Platesare placed onto a vacuum manifold, vacuum applied, and the plates washedthree times with binding buffer containing 0.5M NaCl. The plastic skirtis removed from the plate, the plate allowed to air dry, the wellspunched out and counted. The percent inhibition of binding is calculatedusing the total counts obtained in the absence of any competing compoundand the background binding determined by addition of 100 nM MCP-1 inplace of the test compound.

Antagonism of MCP-1-Induced Calcium Influx

-   (Sullivan, et al. Methods Mol. Biol. 1999, 114, 125-133)

Calcium mobilization is measured using the fluorescent Ca²⁺ indicatordye, Fluo-3. Cells are incubated at 8×10⁵ cells/ml in phosphate-bufferedsaline containing 0.1% bovine serum albumin, 20 mM HEPES buffer, 5 mMglucose, 1% fetal bovine serum, 4 μM Fluo-3 AM and 2.5 mM probenecid for60 minutes at 37° C. Cells used for such calcium assays can includehuman monocytes (Weiner et al., J. Immunol. Methods. 1980, 36, 89) orcell lines which express the endogenous CCR2 receptor, such as THP-1 andMonoMac-6. The cells are then washed three times in phosphate-bufferedsaline containing 0.1% bovine serum albumin, 20 mM HEPES, 5 mM glucoseand 2.5 mM probenecid. The cells are resuspended in phosphate-bufferedsaline containing 0.5% bovine serum albumin, 20 mM HEPES and 2.5 mMprobenecid at a final concentration of 2-4×10⁶ cells/ml. Cells areplated into 96-well, black-wall microplates (100 μl/well) and the platescentrifuged at 200×g for 5 minutes. Various concentrations of compoundare added to the wells (50 μl/well) and after 5 minutes, 50 μl/well ofMCP-1 is added to give a final concentration of 10 nM. Calciummobilization is detected by using a fluorescent-imaging plate reader.The cell monolayer is excited with an argon laser (488 nM) andcell-associated fluorescence measured for 3 minutes, (every second forthe first 90 seconds and every 10 seconds for the next 90 seconds). Dataare generated as arbitrary fluorescence units and the change influorescence for each well determined as the maximum-minimumdifferential. Compound-dependent inhibition is calculated relative tothe response of MCP-1 alone.

Antagonism of MCP-1-Induced Human PBMC Chemotaxis

-   (Bacon et al., Brit. J. Pharmacol. 1988, 95, 966)

Neuroprobe MBA96-96-well chemotaxis chamber, Polyfiltronics MPC 96 wellplate, and Neuroprobe polyvinylpyrrolidone-free polycarbonate PFD58-micron filters are warmed in a 37° C. incubator. Human PeripheralBlood Mononuclear Cells (PBMCs) (Boyum et al., Scand. J. Clin. LabInvest. Suppl. 1968, 97, 31), freshly isolated via the standard ficolldensity separation method, are suspended in DMEM at 1×10⁷ c/ml andwarmed at 37° C. A 60 nM solution of human MCP-1 is also warmed at 37°C. Dilutions of test compounds are made up at 2× the concentrationneeded in DMEM. The PBMC suspension and the 60 nm MCP-1 solution aremixed 1:1 in polypropylene tubes with prewarmed DMEM with or without adilution of the test compounds. These mixtures are warmed in a 37° C.tube warmer. In order to initiate the assay, the MCP-1/compound mixture(400 μL) is added into the wells of the Polyfiltronics MPC 96 well platethat has been placed into the bottom part of the Neuroprobe chemotaxischamber. The 8 micron filter is placed on top of the 96 well plate, arubber gasket is attached to the bottom of the upper chamber, and thechamber is assembled. The cell suspension/compound mixture (200 μl) isadded to the appropriate wells of the upper chamber. The upper chamberis covered with a plate sealer, and the assembled unit is placed in a37° C. incubator for 45 min. After incubation, the plate sealer isremoved and all the remaining cell suspension is aspirated off. Thechamber is disassembled and the filter is removed. The unmigrated cellsare washed away using a gentle stream of phosphate buffered saline, andthe top of the filter is wiped with the tip of a rubber squeegee. Thiswash is repeated twice more. The filter is air dried and then immersedcompletely in Wright Geimsa stain for 45 sec. The filter is washed bysoaking in distilled water for 7 min, and the filter is soaked again for15 sec in fresh distilled water. The filter is air dried. Migrated cellson the filter are quantified by visual microscopy.

Mammalian chemokine receptors provide a target for interfering with orpromoting immune cell function in a mammal, such as a human. Compoundsthat inhibit or promote chemokine receptor function are particularlyuseful for modulating immune cell function for therapeutic purposes.Accordingly, the present invention is directed to compounds which areuseful in the prevention and/or treatment of a wide variety ofinflammatory, infectious, and immunoregulatory disorders and diseases,including asthma and allergic diseases, infection by pathogenic microbes(which, by definition, includes viruses), as well as autoimmunepathologies such as the rheumatoid arthritis and atherosclerosis.

For example, an instant compound which inhibits one or more functions ofa mammalian chemokine receptor (e.g., a human chemokine receptor) may beadministered to inhibit (i.e., reduce or prevent) inflammation orinfectious disease. As a result, one or more inflammatory process, suchas leukocyte migration, adhesion, chemotaxis, exocytosis (e.g., ofenzymes, histamine) or inflammatory mediator release, is inhibited.

In addition, an instant compound that promotesinternalization/desensitization of a mammalian chemokine receptorwithout also inducing its primary function may be administered toinhibit (i.e., reduce or prevent) disease. If one contemplates thedelivery of sufficient compound to cause the loss of receptor expressionon cells through the induction of chemokine receptor internalization,than one can imagine that such a compound would also be useful for thetreatment of the aforementioned inflammatory, allergic and autoimmunediseases.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals, including but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species.The subject treated in the methods above is a mammal, male or female, inwhom modulation of chemokine receptor activity is desired. “Modulation”as used herein is intended to encompass antagonism, partial antagonismand/or partial agonism.

Diseases or conditions of human or other species which can be treatedwith inhibitors of chemokine receptor function, include, but are notlimited to: inflammatory or allergic diseases and conditions, includingrespiratory allergic diseases such as asthma, allergic rhinitis,hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias(e.g., Loeffler's syndrome, chronic eosinophilic pneumonia),eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-typehypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathicpulmonary fibrosis, or ILD associated with rheumatoid arthritis,systemic lupus erythematosus, ankylosing spondylitis, systemicsclerosis, Sjogren's syndrome, polymyositis or dermatomyositis);systemic anaphylaxis or hypersensitivity responses, drug allergies(e.g., to penicillin, cephalosporins), eosinophilia-myalgia syndrome dueto the ingestion of contaminated tryptophan, insect sting allergies;autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis,multiple sclerosis, systemic lupus erythematosus, myasthenia gravis,juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis,Behcet's disease; graft rejection (e.g., in transplantation), includingallograft rejection or graft-versus-host disease; inflammatory boweldiseases, such as Crohn's disease and ulcerative colitis;spondyloarthropathies; scleroderma; psoriasis (including T-cell mediatedpsoriasis) and inflammatory dermatoses such as an dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);eosinophilic myositis, eosinophilic fasciitis; cancers with leukocyteinfiltration of the skin or organs. Other diseases or conditions inwhich undesirable inflammatory responses are to be inhibited can betreated, including, but not limited to, reperfusion injury,atherosclerosis, certain hematologic malignancies, cytokine-inducedtoxicity (e.g., septic shock, endotoxic shock), polymyositis,dermatomyositis. Infectious diseases or conditions of human or otherspecies which can be treated with inhibitors of chemokine receptorfunction, include, but are not limited to, HIV. The compounds of thepresent invention are accordingly useful in the prevention and treatmentof a wide variety of inflammatory, infectious and immunoregulatorydisorders and diseases.

In addition, treatment of the aforementioned inflammatory, allergic andautoimmune diseases can also be contemplated for compounds that promotechemokine receptor internalization without stimulating chemokinereceptor function, particularly if one contemplates the delivery ofsufficient compound to cause the loss of receptor expression on cells.

In another aspect, the instant invention may be used to evaluate theputative specific agonists or antagonists of a G protein coupledreceptor. The present invention is directed to the use of thesecompounds in the preparation and execution of screening assays forcompounds that modulate the activity of chemokine receptors.Furthermore, the compounds of this invention are useful in establishingor determining the binding site of other compounds to chemokinereceptors, e.g., by competitive inhibition or as a reference in an assayto compare its known activity to a compound with an unknown activity.When developing new assays or protocols, compounds according to thepresent invention could be used to test their effectiveness.Specifically, such compounds may be provided in a commercial kit, forexample, for use in pharmaceutical research involving the aforementioneddiseases. The compounds of the instant invention are also useful for theevaluation of putative specific modulators of the chemokine receptors.In addition, one could utilize compounds of this invention to examinethe specificity of G protein coupled receptors that are not thought tobe chemokine receptors, either by serving as examples of compounds whichdo not bind or as structural variants of compounds active on thesereceptors which may help define specific sites of interaction.

The compounds of the present invention are used to treat or preventdisorders selected from rheumatoid arthritis, osteoarthritis, septicshock, atherosclerosis, aneurism, fever, cardiovascular effects,haemodynamic shock, sepsis syndrom, post ischemic reperfusion injury,malaria, Crohn's disease, inflammatory bowel diseases, mycobacterialinfection, meningitis, psoriasis, congestive heart failure, fibroticdiseases, cachexia, graft rejection, autoimmune diseases, skininflammatory diseases, multiple sclerosis, radiation damage, hyperoxicalveolar injury, HIV, HIV dementia, non-insulin dependent diabetesmelitus, asthma, allergic rhinitis, atopic dermatitis, idiopathicpulmonary fibrosis, bullous pemphigoid, helminthic parasitic infections,allergic colitis, eczema, conjunctivitis, transplantation, familialeosinophilia, eosinophilic cellulitis, eosinophilic pneumonias,eosinophilic fasciitis, eosinophilic gastroenteritis, drug inducedeosinophilia, cystic fibrosis, Churg-Strauss syndrome, lymphoma,Hodgkin's disease, colonic carcinoma, Felty's syndrome, sarcoidosis,uveitis, Alzheimer, Glomerulonephritis, and systemic lupuserythematosus.

Furthermore, the compounds are used to treat or prevent inflammatorydisorders selected from osteoarthritis, aneurism, fever, cardiovasculareffects, Crohn's disease, congestive heart failure, autoimmune diseases,HIV-infection, HIV-associated dementia, psoriasis, idiopathic pulmonaryfibrosis, transplant arteriosclerosis, physically- or chemically-inducedbrain trauma, inflammatory bowel disease, alveolitis, colitis, systemiclupus erythematosus, nephrotoxic serum nephritis, glomerularnephritis,asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.

In another aspect of the invention, the compounds are used to treat orprevent inflammatory disorders selected from rheumatoid arthritis,atherosclerosis, and multiple sclerosis.

Combined therapy to prevent and treat inflammatory, infectious andimmunoregulatory disorders and diseases, including asthma and allergicdiseases, as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis, and those pathologies noted above is illustrated bythe combination of the compounds of this invention and other compoundswhich are known for such utilities. For example, in the treatment orprevention of inflammation, the present compounds may be used inconjunction with an anti-inflammatory or analgesic agent such as anopiate agonist, a lipoxygenase inhibitor, a cyclooxygenase-2 inhibitor,an interleukin inhibitor, such as an interleukin-1 inhibitor, a tumornecrosis factor inhibitor, an NMDA antagonist, an inhibitor or nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalanti-inflammatory agent, a phosphodiesterase inhibitor, or acytokine-suppressing anti-inflammatory agent, for example with acompound such as acetaminophen, aspirin, codeine, fentaynl, ibuprofen,indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, asteroidal analgesic, sufentanyl, sunlindac, interferon alpha and thelike. Similarly, the instant compounds may be administered with a painreliever; a potentiator such as caffeine, an H2-antagonist, simethicone,aluminum or magnesium hydroxide; a decongestant such as phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,naphazoline, xylometazoline, propylhexedrine, or levodesoxy-ephedrine;and antitussive such as codeine, hydrocodone, caramiphen,carbetapentane, or dextramethorphan; a diuretic; and a sedating ornon-sedating antihistamine. Likewise, compounds of the present inventionmay be used in combination with other drugs that are used in thetreatment/prevention/suppression or amelioration of the diseases orconditions for which compound of the present invention are useful. Suchother drugs may be administered, by a route and in an amount commonlyused therefore, contemporaneously or sequentially with a compound of thepresent invention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is preferred. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

Examples of other active ingredients that may be combined with acompound of the present invention, either administered separately or inthe same pharmaceutical compositions, include, but are not limited to:(a) integrin antagonists such as those for selectins, ICAMs and VLA-4;(b) steroids such as beclomethasone, methylprednisolone, betamethasone,prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressantssuch as cyclosporin, tacrolimus, rapamycin and other FK-506 typeimmunosuppressants; (d) antihistamines (H1-histamine antagonists) suchas bromopheniramine, chlorpheniramine, dexchlorpheniramine,triprolidine, clemastine, diphenhydramine, diphenylpyraline,tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine,azatadine, cyproheptadine, antazoline, pheniramine pyrilamine,astemizole, terfenadine, loratadine, cetirizine, fexofenadine,descarboethoxyloratadine, and the like; (e) non-steroidalanti-asthmatics such as b2-agonists (terbutaline, metaproterenol,fenoterol, isoetharine, albuteral, bitolterol, and pirbuterol),theophylline, cromolyn sodium, atropine, ipratropium bromide,leukotriene antagonists (zafirlukast, montelukast, pranlukast,iralukast, pobilukast, SKB-102,203), leukotriene biosynthesis inhibitors(zileuton, BAY-1005); (f) non-steroidal antiinflammatory agents (NSAIDs)such as propionic acid derivatives (alminoprofen, benxaprofen, bucloxicacid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen),acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, andzomepirac), fenamic acid derivatives (flufenamic acid, meclofenamicacid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams(isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetylsalicylic acid, sulfasalazine) and the pyrazolones (apazone,bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone);(g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors ofphosphodiesterase type IV (PDE-IV); (I) other antagonists of thechemokine receptors; (j) cholesterol lowering agents such as HMG-COAreductase inhibitors (lovastatin, simvastatin and pravastatin,fluvastatin, atorvsatatin, and other statins), sequestrants(cholestyramine and colestipol), nicotonic acid, fenofibric acidderivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), andprobucol; (k) anti-diabetic agents such as insulin, sulfonylureas,biguanides (metformin), a-glucosidase inhibitors (acarbose) andglitazones (troglitazone ad pioglitazone); (1) preparations ofinterferons (interferon alpha-2a, interferon-2B, interferon alpha-N3,interferon beta-1a, interferon beta-1b, interferon gamma-1b); (m)antiviral compounds such as efavirenz, nevirapine, indinavir,ganciclovir, lamivudine, famciclovir, and zalcitabine; (o) othercompound such as 5-aminosalicylic acid an prodrugs thereof,antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxiccancer chemotherapeutic agents. The weight ratio of the compound of thepresent invention to the second active ingredient may be varied and willdepend upon the effective doses of each ingredient.

Generally, an effective dose of each will be used. Thus, for example,when a compound of the present invention is combined with an NSAID theweight ratio of the compound of the present invention to the NSAID willgenerally range from about 1000:1 to about 1:1000, preferably about200:1 to about 1:200. Combinations of a compound of the presentinvention and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is also meantan amount of a compound of Formula I that, when administered alone or incombination with an additional therapeutic agent to a mammal, iseffective to prevent or ameliorate the thromboembolic disease conditionor the progression of the disease.

Dosage and Formulation

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance. In general, water, a suitableoil, saline, aqueous dextrose (glucose), and related sugar solutions andglycols such as propylene glycol or polyethylene glycols are suitablecarriers for parenteral solutions. Solutions for parenteraladministration preferably contain a water soluble salt of the activeingredient, suitable stabilizing agents, and if necessary, buffersubstances. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Representative useful pharmaceutical dosage-forms for administration ofthe compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 to100 milligrams of the compound of Formula I and about 1 to 7.5milligrams of the second anticoagulant, per kilogram of patient bodyweight. For a tablet dosage form, the compounds of this inventiongenerally may be present in an amount of about 5 to 10 milligrams perdosage unit, and the second anti-coagulant in an amount of about 1 to 5milligrams per dosage unit.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of Formula I and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial which effects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise that as specifically describedherein.

1. A compound of Formula (I)

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein: Z is selected from a bond, —C(O)—, —C(O)NH—, —C(S)NH—, —SO₂—,and —SO₂NH—; X is selected from —NR¹⁷—, —O—, —S—, and —CHR¹⁶NR¹⁷—; R¹ isselected from a C₆₋₁₀ aryl group substituted with 0-5 R⁴ and a 5-10membered heteroaryl system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R⁴; R² is selected from a C₆₋₁₀ arylgroup substituted with 0-5 R⁵ and a 5-10 membered heteroaryl systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R⁵; R³ is selected from H, (CRR)_(q)OH, (CRR)_(q)SH,(CRR)_(q)OR^(3d), (CRR)_(q)S(O)_(p)R^(3d), (CRR)_(r)C(O)R^(3b),(CRR)_(q)NR^(3a)R^(3a), (CRR)_(r)C(O)NR^(3a)R^(3a),(CRR)_(r)C(O)NR^(3a)OR^(3d), (CRR)_(q)SO₂NR^(3a)R^(3a),(CRR)_(r)C(O)OR^(3d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substitutedwith 0-5 R^(3e), and a (CRR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(3e); with the proviso that R³ is not H if R⁶ is H; alternatively,R³ and R¹² join to form a C₃₋₆ cycloalkyl substituted with 0-2 R^(3g) aC₅₋₆ lactam substituted with 0-2 R^(3g), or a C₅₋₆ lactone substitutedwith 0-2 R^(3g); R^(3a), at each occurrence, is independently selectedfrom H, methyl substituted with 0-1 R^(3c), C₂₋₆ alkyl substituted with0-3 R^(3e), C₃₋₈ alkenyl substituted with 0-3 R^(3e), C₃₋₈ alkynylsubstituted with 0-3 R^(3e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(3e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(3e); R^(3b), at each occurrence, isindependently selected from C₁₋₆ alkyl substituted with 0-3 R^(3e), C₂₋₈alkenyl substituted with 0-3 R^(3e), C₂₋₈ alkynyl substituted with 0-3R^(3e), a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2R^(3e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(3e);R^(3c) is independently selected from —C(O)R^(3b), —C(O)OR^(3d),—C(O)NR^(3f)R^(3f), and (CH₂)_(r)phenyl; R^(3d), at each occurrence, isindependently selected from H, methyl, —CF₃, C₂₋₆ alkyl substituted with0-3 R^(3e), C₃₋₆ alkenyl substituted with 0-3 R^(3e), C₃₋₆ alkynylsubstituted with 0-3 R^(3e), a C₃₋₁₀ carbocyclic residue substitutedwith 0-3 R^(3e), and a (CH₂)_(r)-5-6 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(3e); R^(3e), at each occurrence, is selected from C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(3f)R^(3f), and (CH₂)_(r)phenyl; R^(3f), at each occurrence,is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R^(3g) is selectedfrom (CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(3d),(CHR)_(q)S(O)_(p)R^(3d), (CHR)_(r)C(O)R^(3b), (CHR)_(q)NR^(3a)R^(3a),(CHR)_(r)C(O)NR^(3a)R^(3a), (CHR)_(r)C(O)NR^(3a)OR^(3d),(CHR)_(q)SO₂NR^(3a)R^(3a), (CHR)_(r)C(O)OR^(3d), and a (CHR)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(3e); R, at each occurrence,is independently selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CHR)_(r)C(O)NR^(3a)R^(3a), and(CHR)_(r)C(O)OR^(3d), and (CH₂)_(r)phenyl substituted with R^(3e); R⁴,at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CR′R′)_(r)NR^(4a)R^(4a), (CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(4d),(CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(4d),(CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(4b),(CR′R′)_(r)C(O)NR^(4a)R^(4a), (CR′R′)_(r)NR^(4f)C(O)(CR′R′)_(r)R^(4b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(4d), (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(4b),(CR′R′)_(r)NR^(4f)C(O)O(CR′R′)_(r)R^(4d), (CR′R′)_(r)OC(O)NR^(4a)R^(4a),(CR′R′)_(r)NR^(6a)C(S)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR^(4a)C(O)NR^(4a)R^(4a),(CR′R′)_(r)C(═NR^(4f))NR^(4a)R^(4a),(CR′R′)_(r)NHC(═NR^(4f))NR^(4f)R^(4f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(4b), (CR′R′)_(r)S(O)₂NR^(4a)R^(4a),(CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a),(CR′R′)_(r)NR^(4f)S(O)₂(CR′R′)_(r)R^(4b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R₁, C₂₋₈ alkynyl substituted with 0-3 R′, and(CR′R′)_(r)phenyl substituted with 0-3 R^(4e); alternatively, two R⁴ onadjacent atoms on R¹ may join to form a cyclic acetal; R^(4a), at eachoccurrence, is independently selected from H, methyl substituted with0-1R^(4g), C₂₋₆ alkyl substituted with 0-2 R^(5e), C₃₋₈ alkenylsubstituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(4e), and a(CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(4e); R^(4b), at eachoccurrence, is selected from C₁₋₆ alkyl substituted with 0-2 R^(5e),C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with0-2 R^(5e), a (CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3R^(4e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(4e);R^(4d), at each occurrence, is selected from C₃₋₈ alkenyl substitutedwith 0-2 R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), methyl, CF₃,C₂₋₆ alkyl substituted with 0-3 R^(4e), a (CH₂)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-3 R^(4e), and a (CH₂)_(r)-5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(4e); R^(4e), at each occurrence, is selectedfrom C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH,(CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(4f)R^(4f), and (CH₂)_(r)phenyl;R^(4f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆cycloalkyl, and phenyl; R^(4g) is independently selected from—C(O)R^(4b), —C(O)OR^(4d), —C(O)NR^(4f)R^(4f), and (CH₂)_(r)phenyl; R⁵,at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CR′R′)_(r)NR^(5a)R^(5a), (CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(5d),(CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(5d),(CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(5b),(CR′R′)_(r)C(O)NR^(5a)R^(5a), (CR′R′)_(r)NR^(5f)C(O)(CR′R′)_(r)R^(5b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(5d), (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(5b),(CR′R′)_(r)NR^(5f)C(O)O(CR′R′)_(r)R^(5d), (CR′R′)_(r)OC(O)NR^(5a)R^(5a),(CR′R′)_(r)NR^(5a)C(O)NR^(5a)R^(5a),(CR′R′)_(r)C(═NR^(5f))NR^(5a)R^(5a),(CR′R′)_(r)NHC(═NR^(5f))NR^(5f)R^(5f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(5b), (CR′R′)_(r)S(O)₂NR^(5a)R^(5a),(CR′R′)_(r)NR^(5a)S(O)₂NR^(5a)R^(5a),(CR′R′)_(r)NR^(5f)S(O)₂(CR′R′)_(r)R^(5b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and(CR′R′)_(r)phenyl substituted with 0-3 R^(5e); alternatively, two R⁵ onadjacent atoms on R² may join to form a cyclic acetal; R^(5a), at eachoccurrence, is independently selected from H, methyl substituted with0-1 R^(5g), C₂₋₆ alkyl substituted with 0-2 R^(5e), C₃₋₈ alkenylsubstituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(5e), and a(CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(5e); R^(5b), at eachoccurrence, is independently selected from C₁₋₆ alkyl substituted with0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynylsubstituted with 0-2 R^(5e), a (CH₂)_(r)C₃₋₆ carbocyclic residuesubstituted with 0-3 R^(5e), and a (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(5e); R^(5d), at each occurrence, is independently selectedfrom C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substitutedwith 0-2 R^(5e), methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(5e), a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(5e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(5e); R^(5e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(5f)R^(5f), and (CH₂)_(r)phenyl; R^(5f), at each occurrence,is selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl, and phenyl; R^(5g)is independently selected from —C(O)R^(5b), —C(O)OR^(5d),—C(O)NR^(5f)R^(5f), and (CH₂)_(r)phenyl; R′, at each occurrence, isselected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with R^(5e); R⁶, is selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CRR)_(q)OH,(CRR)_(q)SH, (CRR)_(q)OR^(6d), (CRR)_(q)S(O)_(p)R^(6d),(CRR)_(r)C(O)R^(6b), (CRR)_(r)NR^(6a)R^(6a), (CRR)_(r)C(O)NR^(6a)R^(6a),(CRR)_(r)C(O)NR^(6a)OR^(6d), (CRR)SO₂NR^(6a)R^(6a),(CRR)_(r)C(O)OR^(6d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substitutedwith 0-5 R^(6e), and a (CRR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(6e); alternatively, R⁶ and R⁷ join to form a C₃₋₆ cycloalkylsubstituted with 0-2 R^(6g) a 5-6 membered ring lactam substituted with0-2 R^(6g), or a 5-6 membered ring lactone substituted with 0-2 R^(6g);R^(6a), at each occurrence, is independently selected from H, methyl,C₂₋₆ alkyl substituted with 0-3 R^(6e), C₃₋₈ alkenyl substituted with0-3 R^(6e), C₃₋₈ alkynyl substituted with 0-3 R^(6e), (CH₂)_(r)C₃₋₆cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(6e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(6e);R^(6b), at each occurrence, is independently selected from C₁₋₆ alkylsubstituted with 0-3 R^(6e), C₂₋₈ alkenyl substituted with 0-3 R^(6e),C₂₋₈ alkynyl substituted with 0-3 R^(6e), a (CH₂)_(r)—C₃₋₆ carbocyclicresidue substituted with 0-2 R^(6e), and a (CH₂)_(r)-5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(6e); R^(6d), at each occurrence, isindependently selected from H, methyl, —CF₃, C₂₋₆ alkyl substituted with0-3 R^(6e), C₃₋₆ alkenyl substituted with 0-3 R^(6e), C₃₋₆ alkynylsubstituted with 0-3 R^(6e), a C₃₋₁₀ carbocyclic residue substitutedwith 0-3 R^(6e), and a (CH₂)_(r)-5-6 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(6e); R^(6e), at each occurrence, is independently selected fromC₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₁₆ alkyl, SH,(CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;R^(6f), at each occurrence, is independently selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; R^(6g) is selected from (CHR)_(q)OH,(CHR)_(q)SH, (CHR)_(q)OR^(6d), (CHR)_(q)S(O)_(p)R^(6d),(CHR)_(r)C(O)R^(6b), (CHR)_(q)NR^(6a)R^(6a), (CHR)_(r)C(O)NR^(6a)R^(6a),(CHR)_(r)C(O)NR^(6a)OR^(6d), (CHR)_(q)SO₂NR^(6a)R^(6a),(CHR)_(r)C(O)OR^(6d), and a (CHR)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(6e); R⁷, is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(7d),(CRR)_(q)S(O)_(p)R^(7d), (CRR)_(r)C(O)R^(7b), (CRR)_(r)NR^(7a)R^(7a),(CRR)_(r)C(O)NR^(7a)R^(7a), (CRR)_(r)C(O)NR^(7a)OR^(7d),(CRR)_(q)SO₂NR^(7a)R^(7a), (CRR)_(r)C(O)OR^(7d), a (CRR)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(7e), and a (CRR)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(7e); R^(7a), at each occurrence, isindependently selected from H, methyl, C₂₋₆ alkyl substituted with 0-3R^(7e), C₃₋₈ alkenyl substituted with 0-3 R^(7e), C₃₋₈ alkynylsubstituted with 0-3 R^(7e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(7e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(7e); R^(7b), at each occurrence, isindependently selected from C₁₋₆ alkyl substituted with 0-3 R^(7e), C₂₋₈alkenyl substituted with 0-3 R^(7e), C₂₋₈ alkynyl substituted with 0-3R^(7e), a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2R^(7e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(7e);R^(7d), at each occurrence, is independently selected from H, methyl,—CF₃, C₂₋₆ alkyl substituted with 0-3 R^(7e), C₃₋₆ alkenyl substitutedwith 0-3 R^(7e), C₃₋₆ alkynyl substituted with 0-3 R^(7e), a C₃₋₁₀carbocyclic residue substituted with 0-3 R^(7e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(7e); R^(7e), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, —O—C₁₋₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and(CH₂)_(r)phenyl; R^(7f), at each occurrence, is independently selectedfrom H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R⁸ is selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH,(CRR)_(r)OR^(8d), (CRR)_(r)S(O)_(p)R^(8d), (CRR)_(r)C(O)R^(8b),(CRR)_(r)NR^(8a)R^(8a), (CRR)_(r)C(O)NR^(8a)R^(8a),(CRR)_(r)C(O)NR^(8a)OR^(8d), (CRR)_(r)SO₂NR^(8a)R^(8a),(CRR)_(r)C(O)OR^(8d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substitutedwith 0-5 R^(8e), and a (CRR)_(r)-5⁻¹⁰ membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(8e); alternatively, R⁸ and R⁹ join to form a C₃₋₆ cycloalkylsubstituted with 0-2 R^(8g) a 5-6 memebered ring lactam substituted with0-2 R^(8g), or a 5-6 membered ring lactone substituted with 0-2 R^(8g);R^(8a), at each occurrence, is independently selected from H, methyl,C₂₋₆ alkyl substituted with 0-3 R^(8e), C₃₋₈ alkenyl substituted with0-3 R^(8e), C₃₋₈ alkynyl substituted with 0-3 R^(8e), (CH₂)_(r)C₃₋₆cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(8e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(8e);R^(8b), at each occurrence, is independently selected from C₁₋₆ alkylsubstituted with 0-3 R^(8e), C₂₋₈ alkenyl substituted with 0-3 R^(8e),C₂₋₈ alkynyl substituted with 0-3 R^(8e), a (CH₂)_(r)—C₃₋₆ carbocyclicresidue substituted with 0-2 R^(8e), and a (CH₂)_(r)-5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(8e); R^(8d), at each occurrence, isindependently selected from H, methyl, —CF₃, C₂₋₆ alkyl substituted with0-3 R^(8e), C₃₋₆ alkenyl substituted with 0-3 R^(8e), C₃₋₆ alkynylsubstituted with 0-3 R^(8e), a C₃₋₁₀ carbocyclic residue substitutedwith 0-3 R^(8e), and a (CH₂)_(r)-5-6 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(8e); R^(8e), at each occurrence, is independently selected fromC₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,(CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(8f)R^(8f), and (CH₂)_(r)phenyl;R^(8f), at each occurrence, is independently selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; R^(8g) is selected from (CHR)_(q)OH,(CHR)_(q)SH, (CHR)_(q)OR^(8d), (CHR)_(q)S(O)_(p)R^(8d),(CHR)_(r)C(O)R^(8b), (CHR)_(q)NR^(8a)R^(8a), (CHR)_(r)C(O)NR^(8a)R^(8a),(CHR)_(r)C(O)NR^(8a)OR^(8d), (CHR)_(q)SO₂NR^(8a)R^(8a),(CHR)_(r)C(O)OR^(8d), and a (CHR)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(8e); R⁹ is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(9d),(CRR)_(r)S(O)_(p)R^(9d), (CRR)_(r)C(O)R^(9b), (CRR)_(r)NR^(9a)R^(9a),(CRR)_(r)C(O)NR^(9a)R^(9a), (CRR)_(r)C(O)NR^(9a)OR^(9d),(CRR)_(r)SO₂NR^(9a)R^(9a), (CRR)_(r)C(O)OR^(9d), a (CRR)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(9e), and a (CRR)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(9e); R^(9a), at each occurrence, isindependently selected from H, methyl, C₂₋₆ alkyl substituted with 0-3R^(9e), C₃₋₈ alkenyl substituted with 0-3 R^(9e), C₃₋₈ alkynylsubstituted with 0-3 R^(9e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(9e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(9e); R^(9b), at each occurrence, isindependently selected from C₁₋₆ alkyl substituted with 0-3 R^(9e), C₂₋₈alkenyl substituted with 0-3 R^(9e), C₂₋₈ alkynyl substituted with 0-3R^(9e), a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2R^(9e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(9e);R^(9d), at each occurrence, is independently selected from H, methyl,—CF₃, C₂₋₆ alkyl substituted with 0-3 R^(9e), C₃₋₆ alkenyl substitutedwith 0-3 R^(9e), C₃₋₆ alkynyl substituted with 0-3 R^(9e), a C₃₋₁₀carbocyclic residue substituted with 0-3 R^(9e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(9e); R^(9e), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, —O—C₁₋₁₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(9f)R^(9f),and (CH₂)_(r)phenyl; R^(9f), at each occurrence, is independentlyselected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R¹⁰ is selected fromH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH,(CRR)_(r)OR^(10d), (CRR)_(r)S(O)_(p)R^(10d), (CRR)_(r)C(O)R^(10b),(CRR)_(r)NR^(10a)R^(10a), (CRR)_(r)C(O)NR^(10a)R^(10a),(CRR)_(r)C(O)NR^(10a)OR^(10d), (CRR)_(r)SO₂NR^(10a)R^(10a),(CRR)_(r)C(O)OR^(10d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substitutedwith 0-5 R^(10e), and a (CRR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(10e); alternatively, R¹⁰ and R¹¹ join to form a C₃₋₆ cycloalkylsubstituted with 0-2 R^(10g) a 5-6 membered ring lactam substituted with0-2 R^(10g), or a 5-6 membered ring lactone substituted with 0-2R^(10g); R^(10a), at each occurrence, is independently selected from H,methyl, C₂₋₆ alkyl substituted with 0-3 R^(10e), C₃₋₈ alkenylsubstituted with 0-3 R^(10e), C₃₋₈ alkynyl substituted with 0-3 R^(10e),(CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(10e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(10e); R^(10b), at each occurrence, is independently selectedfrom C₁₋₆ alkyl substituted with 0-3 R^(10e), C₂₋₈ alkenyl substitutedwith 0-3 R^(10e), C₂₋₈ alkynyl substituted with 0-3 R^(10e), a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(10e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(10e); R^(10d), ateach occurrence, is independently selected from H, methyl, —CF₃, C₂₋₆alkyl substituted with 0-3 R^(10e), C₃₋₆ alkenyl substituted with 0-3R^(10e), C₃₋₆ alkynyl substituted with 0-3 R^(10e), a C₃₋₁₀ carbocyclicresidue substituted with 0-3 R^(10e), and a (CH₂)_(r)-5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(10e); R^(10e), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, —O—C₁₋₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(10f)R^(10f),and (CH₂)_(r)phenyl; R^(10f), at each occurrence, is independentlyselected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R_(10g) is selectedfrom (CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(10d),(CHR)_(q)S(O)_(p)R^(10d), (CHR)_(r)C(O)R^(10b),(CHR)_(q)NR^(10a)R^(10a), (CHR)_(r)C(O)NR^(10a)R^(10a),(CHR)_(r)C(O)NR^(10a)OR^(10d), (CHR)_(q)SO₂NR^(10a)R^(10a),(CHR)_(r)C(O)OR^(10d), and a (CHR)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(10e); R¹¹, is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(11d),(CRR)_(r)S(O)_(p)R^(11d), (CRR)_(r)C(O)R^(11b),(CRR)_(r)NR^(11a)R^(11a), (CRR)_(r)C(O)NR^(11a)R^(11a),(CRR)_(r)C(O)NR^(11a)OR^(11d), (CRR)_(r)SO₂NR^(11a)R^(11a),(CRR)_(r)C(O)OR^(11d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substitutedwith 0-5 R^(11e), and a (CRR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(11e); R^(11a), at each occurrence, is independently selected fromH, methyl, C₂₋₆ alkyl substituted with 0-3 R^(11e), C₃₋₈ alkenylsubstituted with 0-3 R^(11e), C₃₋₈ alkynyl substituted with 0-3 R^(11e),(CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(11e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(11e); R^(11b), at each occurrence, is independently selectedfrom C₁₋₆ alkyl substituted with 0-3 R^(11e), C₂₋₈ alkenyl substitutedwith 0-3 R^(11e), C₂₋₈ alkynyl substituted with 0-3 R^(11e), a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(11e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(11e); R^(11d), ateach occurrence, is independently selected from H, methyl, —CF₃, C₂₋₆alkyl substituted with 0-3 R^(11e), C₃₋₆ alkenyl substituted with 0-3R^(11e), C₃₋₆ alkynyl substituted with 0-3 R^(11e), a C₃₋₁₀ carbocyclicresidue substituted with 0-3 R^(11e), and a (CH₂)_(r)-5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(11e); R^(11e), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, —O—C₁₋₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(11f)R^(11f),and (CH₂)_(r)phenyl; R^(11f), at each occurrence, is independentlyselected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R¹² is selected fromH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CRR)_(q)OH, (CRR)_(q)SH,(CRR)_(q)OR^(12d), (CRR)_(q)S(O)_(p)R^(12d), (CRR)_(r)C(O)R^(12b),(CRR)_(r)NR^(12a)R^(12a), (CRR)_(r)C(O)NR^(12a)R^(12a),(CRR)_(r)C(O)NR^(12a)OR^(12d), (CRR)_(q)SO₂NR^(12a)R^(12a),(CRR)_(r)C(O)OR^(12d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substitutedwith 0-5 R^(12e), and a (CRR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(12e); R^(12a), at each occurrence, is independently selected fromH, methyl, C₂₋₆ alkyl substituted with 0-3 R^(12e), C₃₋₈ alkenylsubstituted with 0-3 R^(12e), C₃₋₈ alkynyl substituted with 0-3 R^(12e),(CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(12e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(12e); R^(12b), at each occurrence, is independently selectedfrom C₁₋₆ alkyl substituted with 0-3 R^(12e), C₂₋₈ alkenyl substitutedwith 0-3 R^(12e), C₂₋₈ alkynyl substituted with 0-3 R^(12e), a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(12e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(12e); R^(12d) at eachoccurrence, is independently selected from H, methyl, —CF₃, C₂₋₆ alkylsubstituted with 0-3 R^(12e), C₃₋₆ alkenyl substituted with 0-3 R^(12e),C₃₋₆ alkynyl substituted with 0-3 R^(12e), a C₃₋₁₀ carbocyclic residuesubstituted with 0-3 R^(12e), and a (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(12e); R^(12e), at each occurrence, is independently selectedfrom C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br,I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,(CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(12f)R^(12f), and (CH₂)_(r)phenyl;R^(12f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl; R¹⁴ and R^(14a) are independently selected from H, andC₁₋₄alkyl substituted with 0-1 R^(14b), alternatively, R¹⁴ and R^(14a)can join to form a C₃₋₆ cycloalkyl; R^(14b), at each occurrence, isindependently selected from —OH, —SH, —NR^(14c)R^(14c),—C(O)NR^(14c)R^(14c), —NHC(O)R^(14c) and phenyl; R^(14c) is selectedfrom H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R¹⁵ is selected from H, C₁l₄alkyl, and C₃₋₆ cycloalkyl; R¹⁶ is selected from H, C₁₋₄ alkylsubstituted with 0-3 R^(16a), and C₃₋₆ cycloalkyl substituted with 0-3R^(16a); R^(16a) is selected from C₁₋₄ alkyl, —OH, —SH,—NR^(16c)R^(16c), —C(O)NR¹⁶CR^(16c), and —NHC(O)R^(16c); R^(16c) isselected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R¹⁷ is selected from H,C₁₋₄ alkyl, and C₃₋₄ cycloalkyl; n is selected from 1 and 2; l isselected from 0 and 1; m is selected from 0 and 1; p, at eachoccurrence, is selected from 0, 1, or 2; q, at each occurrence, isselected from 1, 2, 3, or 4; and r, at each occurrence, is selected from0, 1, 2, 3, or
 4. 2. A compound of claim 1, wherein Z is selected from abond, —C(O)—, —C(O)NH—, —C(S)NH—, —SO₂—, and —SO₂NH—; X is selected from—NR¹⁷—, —O—, —S—, and —CHR¹⁶NR¹⁷—; R¹ is selected from a C₆₋₁₀ arylgroup substituted with 0-5 R⁴ and a 5-10 membered heteroaryl systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R⁴; R² is selected from a C₆₋₁₀ aryl group substituted with 0-5 R⁵and a 5-10 membered heteroaryl system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R⁵; R³ is selected from(CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(3d), (CRR)_(q)S(O)_(p)R^(3d),(CRR)_(r)C(O)R^(3b), (CRR)_(q)NR^(3a)R^(3a), (CRR)_(r)C(O)NR^(3a)R^(3a),(CRR)_(r)C(O)NR^(3a)OR^(3d), (CRR)_(q)SO₂NR^(3a)R^(3a),(CRR)_(r)C(O)OR^(3d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substitutedwith 0-5 R^(3e), and a (CRR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(3e); alternatively, R³ and R¹² join to form a C₃₋₆ cycloalkylsubstituted with 0-2 R^(3g) a C₅₋₆ lactam substituted with 0-2 R^(3g),or a C₅₋₆ lactone substituted with 0-2 R^(3g); R^(3a), at eachoccurrence, is independently selected from H, methyl substituted with0-1 R^(3c), C₂₋₆ alkyl substituted with 0-3 R^(3e), C₃₋₈ alkenylsubstituted with 0-3 R^(3e), C₃₋₈ alkynyl substituted with 0-3 R^(3e),(CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(3e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(3e); R^(3b), at each occurrence, is independently selectedfrom C₁₋₆ alkyl substituted with 0-3 R^(3e), C₂₋₈ alkenyl substitutedwith 0-3 R^(3e), C₂₋₈ alkynyl substituted with 0-3 R^(3e), a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(3e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(3e); R^(3c) isindependently selected from —C(O)R^(3b), —C(O)OR^(3d),—C(O)NR^(3f)R^(3f), and (CH₂)_(r)phenyl; R^(3d), at each occurrence, isindependently selected from H, methyl, —CF₃, C₂₋₆ alkyl substituted with0-3 R^(3e), C₃₋₆ alkenyl substituted with 0-3 R^(3e), C₃₋₆ alkynylsubstituted with 0-3 R^(3e), a C₃₋₁₀ carbocyclic residue substitutedwith 0-3 R^(3e), and a (CH₂)_(r)-5-6 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(3e); R^(3e), at each occurrence, is selected from C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(3f)R^(3f), and (CH₂)_(r)phenyl; R^(3f), at each occurrence,is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R^(3g) is selectedfrom (CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(3d),(CHR)_(q)S(O)_(p)R^(3d), (CHR)_(r)C(O)R^(3b), (CHR)_(q)NR^(3a)R^(3a),(CHR)_(r)C(O)NR^(3a)R^(3a), (CHR)_(r)C(O)NR^(3a)OR^(3d),(CHR)_(q)SO₂NR^(3a)R^(3a), (CHR)_(r)C(O)OR^(3d), and a (CHR)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(3e); R, at each occurrence,is independently selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CHR)_(r)C(O)NR^(3a)R^(3a), and(CHR)_(r)C(O)OR^(3d), and (CH₂)_(r)phenyl substituted with R^(3e); R⁴,at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CR′R′)_(r)NR^(4a)R^(4a), (CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(4d),(CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(4d),(CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(4b),(CR′R′)_(r)C(O)NR^(4a)R^(4a), (CR′R′)_(r)NR^(4f)C(O)(CR′R′)_(r)R^(4b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(4d), (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(4b),(CR′R′)_(r)NR^(4f)C(O)O(CR′R′)_(r)R^(4d), (CR′R′)_(r)OC(O)NR^(4a)R^(4a),(CR′R′)_(r)NR^(6a)C(S)NR^(6a)(CR′R′)_(r)R^(6d),(CR′R′)_(r)NR^(4a)C(O)NR^(4a)R^(4a),(CR′R′)_(r)C(═NR^(4f))NR^(4a)R^(4a),(CR′R′)_(r)NHC(═NR^(4f))NR^(4f)R^(4f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(4b), (CR′R′)_(r)S(O)₂NR^(4a)R^(4a),(CR′R′)_(r)NR^(6f)S(O)₂NR^(6a)R^(6a),(CR′R′)_(r)NR^(4f)S(O)₂(CR′R′)_(r)R^(4b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and(CR′R′)_(r)phenyl substituted with 0-3 R^(4e); alternatively, two R⁴ onadjacent atoms on R¹ may join to form a cyclic acetal; R^(4a), at eachoccurrence, is independently selected from H, methyl substituted with0-1R^(4g), C₂₋₆ alkyl substituted with 0-2 R^(5e), C₃₋₈ alkenylsubstituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(4e), and a(CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(4e); R^(4b), at eachoccurrence, is selected from C₁₋₆ alkyl substituted with 0-2 R^(5e),C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with0-2 R^(5e), a (CH₂)_(r)C₃₋₆ carbocyclic residue substituted with 0-3R^(4e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-2 R^(4e);R^(4d), at each occurrence, is selected from C₃₋₈ alkenyl substitutedwith 0-2 R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), methyl, CF₃,C₂₋₆ alkyl substituted with 0-3 R^(4e), a (CH₂)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0-3 R^(4e), and a (CH₂)_(r)-5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(4e); R^(4e), at each occurrence, is selectedfrom C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH,(CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(4f)R^(4f), and (CH₂)_(r)phenyl;R^(4f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆cycloalkyl, and phenyl; R^(4g) is independently selected from—C(O)R^(4b), —C(O)OR^(4d), —C(O)NR^(4f)R^(4f), and (CH₂)_(r)phenyl; R⁵,at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CR′R′)_(r)NR^(5a)R^(5a), (CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(5d),(CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(5d),(CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)(CR′R′)_(r)R^(5b),(CR′R′)_(r)C(O)NR^(5a)R^(5a), (CR′R′)_(r)NR^(5f)C(O)(CR′R′)_(r)R^(5b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(5d), (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(5b),CR′R′)_(r)NR^(5f)C(O)O(CR′R′)_(r)R^(5d), (CR′R′)_(r)OC(O)NR^(5a)R^(5a),(CR′R′)_(r)NR^(5a)C(O)NR^(5a)R^(5a),(CR′R′)_(r)C(═NR^(5f))NR^(5a)R^(5a),(CR′R′)_(r)NHC(═NR^(5f))NR^(5f)R^(5f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(5b), (CR′R′)_(r)S(O)₂NR^(5a)R^(5a),(CR′R′)_(r)NR^(5a)S(O)₂NR^(5a)R^(5a),(CR′R′)_(r)NR^(5f)S(O)₂(CR′R′)_(r)R^(5b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0-3 R′, C₂₋₈ alkynyl substituted with 0-3 R′, and(CR′R′)_(r)phenyl substituted with 0-3 R^(5e); alternatively, two R⁵ onadjacent atoms on R² may join to form a cyclic acetal; R^(5a), at eachoccurrence, is independently selected from H, methyl substituted with0-1 R^(5g), C₂₋₆ alkyl substituted with 0-2 R^(5e), C₃₋₈ alkenylsubstituted with 0-2 R^(5e), C₃₋₈ alkynyl substituted with 0-2 R^(5e), a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5 R^(5e), and a(CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-2 R^(5e); R^(5b), at eachoccurrence, is independently selected from C₁₋₆ alkyl substituted with0-2 R^(5e), C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynylsubstituted with 0-2 R^(5e), a (CH₂)_(r)C₃₋₆ carbocyclic residuesubstituted with 0-3 R^(5e), and a (CH₂)_(r)-5-6 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-2 R^(5e); R^(5d), at each occurrence, is independently selectedfrom C₃₋₈ alkenyl substituted with 0-2 R^(5e), C₃₋₈ alkynyl substitutedwith 0-2 R^(5e), methyl, CF₃, C₂₋₆ alkyl substituted with 0-3 R^(5e), a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-3 R^(5e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(5e); R^(5e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(5f)R^(5f), and (CH₂)_(r)phenyl; R^(5f), at each occurrence,is selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl, and phenyl; R^(5g)is independently selected from —C(O)R^(5b), —C(O)OR^(5d),—C(O)NR^(5f)R^(5f), and (CH₂)_(r)phenyl; R′, at each occurrence, isselected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, and (CH₂)_(r)phenyl substituted with R^(5e); R⁶, is selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CRR)_(q)OH,(CRR)_(q)SH, (CRR)_(q)OR^(6d), (CRR)_(q)S(O)_(p)R^(6d),(CRR)_(r)C(O)R^(6b), (CRR)_(r)NR^(6a)R^(6a), (CRR)_(r)C(O)NR^(6a)R^(6a),(CRR)_(r)C(O)NR^(6a)OR^(6d), (CRR)SO₂NR^(6a)R^(6a),(CRR)_(r)C(O)OR^(6d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substitutedwith 0-5 R^(6e), and a (CRR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(6e); alternatively, R⁶ and R⁷ join to form a C₃₋₆ cycloalkylsubstituted with 0-2 R^(6g) a 5-6 membered ring lactam substituted with0-2 R^(6g), or a 5-6 membered ring lactone substituted with 0-2 R^(6g);R^(6a), at each occurrence, is independently selected from H, methyl,C₂₋₆ alkyl substituted with 0-3 R^(6e), C₃₋₈ alkenyl substituted with0-3 R^(6e), C₃₋₈ alkynyl substituted with 0-3 R^(6e), (CH₂)_(r)C₃₋₆cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(6e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(6e);R^(6b), at each occurrence, is independently selected from C₁₋₆ alkylsubstituted with 0-3 R^(6e), C₂₋₈ alkenyl substituted with 0-3 R^(6e),C₂₋₈ alkynyl substituted with 0-3 R^(6e), a (CH₂)_(r)—C₃₋₆ carbocyclicresidue substituted with 0-2 R^(6e), and a (CH₂)_(r)-5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(6e); R^(6d), at each occurrence, isindependently selected from H, methyl, —CF₃, C₂₋₆ alkyl substituted with0-3 R^(6e), C₃₋₆ alkenyl substituted with 0-3 R^(6e), C₃₋₆ alkynylsubstituted with 0-3 R^(6e), a C₃₋₁₀ carbocyclic residue substitutedwith 0-3 R^(6e), and a (CH₂)_(r)-5-6 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(6e); R^(6e), at each occurrence, is independently selected fromC₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,(CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;R^(6f), at each occurrence, is independently selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; R^(6g) is selected from (CHR)_(q)OH,(CHR)_(q)SH, (CHR)_(q)OR^(6d), (CHR)_(q)S(O)_(p)R^(6d),(CHR)_(r)C(O)R^(6b), (CHR)_(q)NR^(6a)R^(6a), (CHR)_(r)C(O)NR^(6a)R^(6a),(CHR)_(r)C(O)NR^(6a)OR^(6d), (CHR)_(q)SO₂NR^(6a)R^(6a),(CHR)_(r)C(O)OR^(6d), and a (CHR)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(6e); R⁷, is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(7d),(CRR)_(q)S(O)_(p)R^(7d), (CRR)_(r)C(O)R^(7b), (CRR)_(r)NR^(7a)R^(7a),(CRR)_(r)C(O)NR^(7a)R^(7a), (CRR)_(r)C(O)NR^(7a)OR^(7d),(CRR)_(q)SO₂NR^(7a)R^(7a), (CRR)_(r)C(O)OR^(7d), a (CRR)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(7e), and a (CRR)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(7e); R^(7a), at each occurrence, isindependently selected from H, methyl, C₂₋₆ alkyl substituted with 0-3R^(7e), C₃₋₈ alkenyl substituted with 0-3 R^(7e), C₃₋₈ alkynylsubstituted with 0-3 R^(7e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(7e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(7e); R^(7b), at each occurrence, isindependently selected from C₁₋₆ alkyl substituted with 0-3 R^(7e), C₂₋₈alkenyl substituted with 0-3 R^(7e), C₂₋₈ alkynyl substituted with 0-3R^(7e), a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2R^(7e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(7e);R^(7d), at each occurrence, is independently selected from H, methyl,—CF₃, C₂₋₆ alkyl substituted with 0-3 R^(7e), C₃₋₆ alkenyl substitutedwith 0-3 R^(7e), C₃₋₆ alkynyl substituted with 0-3 R^(7e), a C₃₋₁₀carbocyclic residue substituted with 0-3 R^(7e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(7e); R^(7e), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, —O—C₁₋₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and(CH₂)_(r)phenyl; R^(7f), at each occurrence, is independently selectedfrom H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R⁸ is selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH,(CRR)_(r)OR^(8d), (CRR)_(r)S(O)_(p)R^(8d), (CRR)_(r)C(O)R^(8b),(CRR)_(r)NR^(8a)R^(8a), (CRR)_(r)C(O)NR^(8a)R^(8a),(CRR)_(r)C(O)NR^(8a)OR^(8d), (CRR)_(r)SO₂NR^(8a)R^(8a),(CRR)_(r)C(O)OR^(8d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substitutedwith 0-5 R^(8e), and a (CRR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(8e); alternatively, R⁸ and R⁹ join to form a C₃₋₆ cycloalkylsubstituted with 0-2 R^(8g) a 5-6 memebered ring lactam substituted with0-2 R^(8g), or a 5-6 membered ring lactone substituted with 0-2 R^(8g);R^(8a), at each occurrence, is independently selected from H, methyl,C₂₋₆ alkyl substituted with 0-3 R^(8e), C₃₋₈ alkenyl substituted with0-3 R^(8e), C₃₋₈ alkynyl substituted with 0-3 R^(8e), (CH₂)_(r)C₃₋₆cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0-5R^(8e), and a (CH₂)_(r)-5-10 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(8e);R^(8b), at each occurrence, is independently selected from C₁₋₆ alkylsubstituted with 0-3 R^(8e), C₂₋₈ alkenyl substituted with 0-3 R^(8e),C₂₋₈ alkynyl substituted with 0-3 R^(8e), a (CH₂)_(r)—C₃₋₆ carbocyclicresidue substituted with 0-2 R^(8e), and a (CH₂)_(r)-5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(8e); R^(8d), at each occurrence, isindependently selected from H, methyl, —CF₃, C₂₋₆ alkyl substituted with0-3 R^(8e), C₃₋₆ alkenyl substituted with 0-3 R^(8e), C₃₋₆ alkynylsubstituted with 0-3 R^(8e), a C₃₋₁₀ carbocyclic residue substitutedwith 0-3 R^(8e), and a (CH₂)_(r)-5-6 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(8e); R^(8e), at each occurrence, is independently selected fromC₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,(CH₂)_(r)SC₁₋₁₅ alkyl, (CH₂)_(r)NR^(8f)R^(8f), and (CH₂)_(r)phenyl;R^(8f), at each occurrence, is independently selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; R^(8g) is selected from (CHR)_(q)OH,(CHR)_(q)SH, (CHR)_(q)OR^(8d), (CHR)_(q)S(O)_(p)R^(8d),(CHR)_(r)C(O)R^(8b), (CHR)_(q)NR^(8a)R^(8a), (CHR)_(r)C(O)NR^(8a)R^(8a),(CHR)_(r)C(O)NR^(8a)OR^(8d), (CHR)_(q)SO₂NR^(8a)R^(8a),(CHR)_(r)C(O)OR^(8d), and a (CHR)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(8e); R⁹ is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(9d),(CRR)_(r)S(O)_(p)R^(9d), (CRR)_(r)C(O)R^(9b), (CRR)_(r)NR^(9a)R^(9a),(CRR)_(r)C(O)NR^(9a)R^(9a), (CRR)_(r)C(O)NR^(9a)OR^(9d),(CRR)_(r)SO₂NR^(9a)R^(9a), (CRR)_(r)C(O)OR^(9d), a (CRR)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(9e), and a (CRR)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(9e); R^(9a), at each occurrence, isindependently selected from H, methyl, C₂₋₆ alkyl substituted with 0-3R^(9e), C₃₋₈ alkenyl substituted with 0-3 R^(9e), C₃₋₈ alkynylsubstituted with 0-3 R^(9e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(9e), and a (CH₂)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(9e); R^(9b), at each occurrence, isindependently selected from C₁₋₆ alkyl substituted with 0-3 R^(9e), C₂₋₈alkenyl substituted with 0-3 R^(9e), C₂₋₈ alkynyl substituted with 0-3R^(9e), a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2R^(9e), and a (CH₂)_(r)-5-6 membered heterocyclic system containing 1-4heteroatoms selected from N, O, and S, substituted with 0-3 R^(9e);R^(9d), at each occurrence, is independently selected from H, methyl,—CF₃, C₂₋₆ alkyl substituted with 0-3 R^(9e), C₃₋₆ alkenyl substitutedwith 0-3 R^(9e), C₃₋₆ alkynyl substituted with 0-3 R^(9e), a C₃₋₁₀carbocyclic residue substituted with 0-3 R^(9e), and a (CH₂)_(r)-5-6membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(9e); R^(9e), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, —O—C₁₋₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(9f)R^(9f), and(CH₂)_(r)phenyl; R^(9f), at each occurrence, is independently selectedfrom H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R¹⁰ is selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH,(CRR)_(r)OR^(10d), (CRR)_(r)S(O)_(p)R^(10d), (CRR)_(r)C(O)R^(10b),(CRR)_(r)NR^(10a)R^(10a), (CRR)_(r)C(O)NR^(10a)R^(10a),(CRR)_(r)C(O)NR^(10a)OR^(10d), (CRR)_(r)SO₂NR^(10a)R^(10a),(CRR)_(r)C(O)OR^(10d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substitutedwith 0-5 R^(10e), and a (CRR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(10e); alternatively, R¹⁰ and R¹¹l join to form a C₃₋₆ cycloalkylsubstituted with 0-2 R^(10g) a 5-6 membered ring lactam substituted with0-2 R^(10g), or a 5-6 membered ring lactone substituted with 0-2R^(10g); R^(10a), at each occurrence, is independently selected from H,methyl, C₂₋₆ alkyl substituted with 0-3 R^(10e), C₃₋₈ alkenylsubstituted with 0-3 R^(10e), C₃₋₈ alkynyl substituted with 0-3 R^(10e),(CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(10e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(10e); R^(10b), at each occurrence, is independently selectedfrom C₁₋₆ alkyl substituted with 0-3 R^(10e), C₂₋₈ alkenyl substitutedwith 0-3 R^(10e), C₂₋₈ alkynyl substituted with 0-3 R^(10e), a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(10e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(10e); R^(10d), ateach occurrence, is independently selected from H, methyl, —CF₃, C₂₋₆alkyl substituted with 0-3 R^(10e), C₃₋₆ alkenyl substituted with 0-3R^(10e), C₃₋₆ alkynyl substituted with 0-3 R^(10e), a C₃₋₁₀ carbocyclicresidue substituted with 0-3 R^(10e), and a (CH₂)_(r)-5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(10e); R^(10e), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, —O—C₁₋₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(10f)R^(10f),and (CH₂)_(r)phenyl; R^(10f), at each occurrence, is independentlyselected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R^(10g) is selectedfrom (CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(10d),(CHR)_(q)S(O)_(p)R^(10d), (CHR)_(r)C(O)R^(10b),(CHR)_(q)NR^(10a)R^(10a), (CHR)_(r)C(O)NR^(10a)R^(10a),(CHR)_(r)C(O)NR^(10a)OR^(10d), (CHR)_(q)SO₂NR^(10a)R^(10a),(CHR)_(r)C(O)OR^(10d), and a (CHR)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(10e); R¹¹, is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(11d),(CRR)_(r)S(O)_(p)R^(11d), (CRR)_(r)C(O)R^(11b), (CRR)_(r)NR^(11a)R^(11a)(CRR)_(r)C(O)NR^(11a)R^(11a), (CRR)_(r)C(O)NR^(11a)OR^(11d),(CRR)_(r)SO₂NR^(11a)R^(11a), (CRR)_(r)C(O)OR^(11d), a (CRR)_(r)—C₃₋₁₀carbocyclic residue substituted with 0-5 R^(11e), and a (CRR)_(r)-5-10membered heterocyclic system containing 1-4 heteroatoms selected from N,O, and S, substituted with 0-3 R^(11e); R^(11a), at each occurrence, isindependently selected from H, methyl, C₂₋₆ alkyl substituted with 0-3R^(11e), C₃₋₈ alkenyl substituted with 0-3 R^(11e), C₃₋₈ alkynylsubstituted with 0-3 R^(11e), (CH₂)_(r)C₃₋₆ cycloalkyl, a(CH₂)_(r)—C³-10 carbocyclic residue substituted with 0-5 R^(11e), and a(CH₂)_(r)-5-10 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(11e); R^(11b), ateach occurrence, is independently selected from C₁₋₆ alkyl substitutedwith 0-3 R^(11e), C₂₋₈ alkenyl substituted with 0-3 R^(11e), C₂₋₈alkynyl substituted with 0-3 R^(11e), a (CH₂)_(r)—C₃₋₆ carbocyclicresidue substituted with 0-2 R^(11e), and a (CH₂)_(r)-5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(11e); R^(11d), at each occurrence, isindependently selected from H, methyl, —CF₃, C₂₋₆ alkyl substituted with0-3 R^(11e), C₃₋₆ alkenyl substituted with 0-3 R^(11e), C₃₋₆ alkynylsubstituted with 0-3 R^(11e), a C₃₋₁₀ carbocyclic residue substitutedwith 0-3 R^(11e), and a (CH₂)_(r)-5-6 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(11e); R^(11e), at each occurrence, is independently selected fromC₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,(CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl;R^(11f), at each occurrence, is independently selected from H, C₁₋₆alkyl, and C₃₋₆ cycloalkyl; R¹² is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(12d),(CRR)_(q)S(O)_(p)R^(12d), (CRR)_(r)C(O)R^(12b),(CRR)_(r)NR^(12a)R^(12a), (CRR)_(r)C(O)NR^(12a)R^(12a),(CRR)_(r)C(O)NR^(12a)OR^(12d), (CRR)_(q)SO₂NR^(12a)R^(12a),(CRR)_(r)C(O)OR^(12d), a (CRR)_(r)—C₃₋₁O carbocyclic residue substitutedwith 0-5 R^(12e), and a (CRR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(12e); R^(12a), at each occurrence, is independently selected fromH, methyl, C₂₋₆ alkyl substituted with 0-3 R^(12e), C₃₋₈ alkenylsubstituted with 0-3 R^(12e), C₃₋₈ alkynyl substituted with 0-3 R^(12e),(CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-5 R^(12e), and a (CH₂)_(r)-5-10 membered heterocyclicsystem containing 1-4 heteroatoms selected from N, O, and S, substitutedwith 0-3 R^(12e); R^(12b), at each occurrence, is independently selectedfrom C₁₋₆ alkyl substituted with 0-3 R^(12e), C₂₋₈ alkenyl substitutedwith 0-3 R^(12e), C₂₋₈ alkynyl substituted with 0-3 R^(12e), a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-2 R^(12e), and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, substituted with 0-3 R^(12e); R^(12d), ateach occurrence, is independently selected from H, methyl, —CF₃, C₂₋₆alkyl substituted with 0-3 R^(12e), C₃₋₆ alkenyl substituted with 0-3R^(12e), C₃₋₆ alkynyl substituted with 0-3 R^(12e), a C₃₋₁₀ carbocyclicresidue substituted with 0-3 R^(12e), and a (CH₂)_(r)-5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-3 R^(12e); R^(12e), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, —O—C₁₋₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(12f)R^(12f),and (CH₂)_(r)phenyl; R^(12f), at each occurrence, is selected from H,C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R¹⁴ and R^(14a) are independentlyselected from H, and C₁₋₄alkyl substituted with 0-1 R^(14b),alternatively, R¹⁴ and R^(14a) can join to form a C₃₋₆ cycloalkyl;R^(14b), at each occurrence, is independently selected from —OH, —SH,—NR^(14c)R^(14c), —C(O)NR^(14c)R^(14c), —NHC(O)R^(14c) and phenyl;R^(14c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R¹⁵ isselected from H, C₁₋₄ alkyl, and C₃₋₆ cycloalkyl; R¹⁶ is selected fromH, C₁₋₄ alkyl substituted with 0-3 R^(16a), and C₃₋₆ cycloalkylsubstituted with 0-3 R^(16a); R^(16a) is selected from C₁₋₄ alkyl, —OH,—SH, —NR^(16c)R^(16c), —C(O)NR^(16c)R^(16c), and —NHC(O)R^(16c); R^(16c)is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R¹⁷ is selected fromH, C₁₋₄ alkyl, and C₃₋₄ cycloalkyl; n is selected from 1 and 2; l isselected from 0 and 1; m is selected from 0 and 1; p, at eachoccurrence, is selected from 0, 1, or 2; q, at each occurrence, isselected from 1, 2, 3, or 4; and r, at each occurrence, is selected from0, 1, 2, 3, or
 4. 3. The compound of claim 2, wherein: R¹⁴ and R^(14a)are H; R¹⁵ is H; and n is
 1. 4. The compound of claim 3, wherein: R¹⁶ isselected from H, C₁₋₄ alkyl substituted with 0-1 R^(16a), wherein thealkyl is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,and s-butyl, and C₃₋₄ cycloalkyl substituted with 0-3 R¹⁶a wherein thecycloalkyl is selected from cyclopropyl and cyclobutyl; R^(16a) isselected from methyl, ethyl, propyl, i-propyl, —OH, —SH,NR^(16c)R^(16c), —C(O)NR^(16c)R^(16c), and —NHC(O)R^(16c); and R¹⁷ isselected from H, methyl, ethyl, propyl, and i-propyl.
 5. The compound ofclaim 4, wherein: R⁹ and R¹¹ are H; and R⁸ and R¹⁰ are independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue wherein the carbocyclic residue isselected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyland naphthyl.
 6. The compound of claim 5, wherein: R³ is selected from(CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(3d), (CRR)_(q)S(O)_(p)R^(3d),(CRR)_(r)C(O)R^(3b), (CRR)_(q)R^(3a)R^(3a), (CRR)_(r)C(O)NR^(3a)R^(3a),(CRR)_(r)C(O)NR^(3a)OR^(3d), (CRR)_(q)SO₂NR^(3a)R^(3a),(CRR)_(r)C(O)OR^(3d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substitutedwith 0-5 R^(3e), and a (CRR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(3e) wherein the heterocyclic system is selected from pyridinyl,thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl,isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, 1,2,4-triazolyl,1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl; R⁶ is selected from H, (CRR)_(q)OH,(CRR)_(q)SH, (CRR)_(q)OR^(6d), (CRR)_(q)S(O)_(p)R^(6d),(CRR)_(r)C(O)R^(6b), (CRR)_(q)NR^(6a)R^(6a), (CRR)_(r)C(O)NR^(6a)R^(6a),(CRR)_(r)C(O)NR^(6a)OR^(6d), (CRR)_(q)SO₂NR^(6a)R^(6a),(CRR)_(r)C(O)OR^(6d), a (CRR)_(r)—C₆₋₁₀ carbocyclic residue substitutedwith 0-5 R^(6e), and a (CRR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-6 R^(6e) wherein the heterocyclic system is selected from pyridinyl,thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl,isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, 1,2,4-triazolyl,1,2,6-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl; R⁷ is H; R¹² is selected from H, methyl,ethyl, and propyl; alternatively, R³ and R¹² join to form a C₃₋₆cycloalkyl substituted with 0-2 R^(3g) a C₅₋₆ lactam substituted with0-2 R^(3g), or a C₅₋₆ lactone substituted with 0-2 R^(3g).
 7. Thecompound of claim 6, wherein: R¹ is selected from phenyl substitutedwith 0-3 R⁴ and a 5-10 membered heteroaryl system substituted with 0-3R⁴, wherein the heteroaryl is selected from benzimidazolyl,benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazalonyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl,isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,thiazolyl, thienyl, and tetrazolyl; R² is selected from phenylsubstituted with 0-3 R⁵ and a 5-10 membered heteroaryl system containing1-4 heteroatoms substituted with 0-3 R⁵, wherein the heteroaryl systemis selected from benzimidazolyl, benzofuranyl, benzothiofuranyl,benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl,imidazolyl, indazolyl, indolyl, isoquinolinyl isothiazolyl, isoxazolyl,oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl,pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and tetrazolyl.8. The compound of claim 7, wherein: X is CHR¹⁶R¹⁷; R⁴, at eachoccurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CR′R′)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CR′R′)_(r)NR^(4a)R^(4a), (CR′R′)_(r)OH, (CR′R′)_(r)OR^(4d),(CR′R′)_(r)SH, (CR′R′)_(r)SR^(4d), (CR′R′)_(r)C(O)OH,(CR′R′)_(r)C(O)R^(4b), (CR′R′)_(r)C(O)NR^(4a)R^(4a),(CR′R′)_(r)NR^(4f)C(O)R^(4b), (CR′R′)_(r)C(O)OR^(4d),(CR′R′)_(r)OC(O)R^(4b), (CR′R′)_(r)NR^(4f)C(O)OR^(4d),(CR′R′)_(r)OC(O)NR^(4a)R^(4a), (CR′R′)_(r)NR^(4a)C(O)NR^(4a)R^(4a),(CR′R′)_(r)S(O)_(p)R^(4b), (CR′R′)_(r)S(O)₂NR^(4a)R^(4a),(CR′R′)_(r)NR^(4f)S(O)₂R^(4b), (CR′R′)_(r)NR^(4f)S(O)₂ NR^(4a)R^(4a),C₁₋₆ haloalkyl, and (CR′R′)_(r)phenyl substituted with 0-3 R^(4e);alternatively, two R⁴ on adjacent atoms join to form —O— (CH₂)—O—;R^(4a), at each occurrence, is independently selected from H, methyl,ethyl, propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl,hexyl, allyl, propargyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residueselected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;R^(4b), at each occurrence, is selected from methyl, ethyl, propyl,i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl, allyl,propargyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0-3R^(4e), wherein the carbocyclic residue is selected from cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl, and a (CH₂)_(r)-5-6 memberedheterocyclic system containing 1-4 heteroatoms selected from N, O, andS, substituted with 0-2 R^(4e), wherein the heterocyclic system isselected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl,benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl,indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl,pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl,thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; R^(4d), at eachoccurrence, is selected from H, methyl, CF₃, ethyl, propyl, i-propyl,butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl, allyl, propargyl, and a(CH₂)_(r)C₃₋₆ carbocyclic residue selected from cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl; R^(4e), at each occurrence, is selected fromC₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F,Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH,(CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(4f)R^(4f), and (CH₂)_(r)phenyl;R^(4f), at each occurrence, is selected from H, methyl, ethyl, propyl,i-propyl, butyl, and cyclopropyl, cyclobutyl, and phenyl; R⁵, at eachoccurrence, is selected from methyl, ethyl, propyl, i-propyl, butyl,i-butyl, s-butyl, t-butyl, pentyl, hexyl, (CR′R′)_(r)C₃₋₆ cycloalkyl,Cl, Br, I, F, NO₂, CN, (CR′R′)_(r)NR^(5a)R^(5a), (CR′R′)_(r)OH,(CR′R′)_(r)OR^(5d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)SR^(5d),(CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)R^(5b), (CR′R′)_(r)C(O)NR^(5a)R^(5a),(CR′R′)_(r)NR^(5f)C(O)R^(5b), (CR′R′)_(r)C(O)OR^(5d),(CR′R′)_(r)OC(O)R^(5b), (CR′R′)_(r)NR^(5f)C(O)OR^(5d),(CR′R′)_(r)OC(O)NR^(5a)R^(5a), (CR′R′)_(r)NR^(5a)C(O)NR^(5a)R^(5a),(CR′R′)_(r)NR^(7a)C(O)NR^(7a)R^(7a),(CR′R′)_(r)NR^(7a)C(O)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)S(O)_(p)R^(5b),(CR′R′)_(r)S(O)₂NR^(5a)R^(5a), (CR′R′)_(r)NR^(5f)S(O)₂R^(5b), C₁₋₆haloalkyl, and (CHR′)_(r)phenyl substituted with 0-3 R^(5e);alternatively, two R⁵ on adjacent atoms join to form —O—(CH₂)—O—;R^(5a), at each occurrence, is independently selected from H, methyl,ethyl, propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl,hexyl, allyl, propargyl, and a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0-1 R^(5e), wherein the carbocyclic residue is selectedfrom cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl andnaphthyl; R^(5b), at each occurrence, is selected from methyl, ethyl,propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl,allyl, propargyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl; and a(CH₂)_(r)-5-6 membered heterocyclic system containing 1-4 heteroatomsselected from N, O, and S, wherein the heterocyclic system is selectedfrom pyridinyl, thiophenyl, furanyl, indazolyl, azetidinyl,benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl,benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl,indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, morphlinyl,piperidinyl, pyrrolyl, 2,5-dihydropyrrolyl, pyrrazolyl, 1,2,4-triazolyl,1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl,pyrazinyl, and pyrimidinyl; R^(5d), at each occurrence, is selected fromH, methyl, CF₃, ethyl, propyl, i-propyl, butyl, s-butyl, i-butyl,t-butyl, pentyl, hexyl, allyl, propargyl, and a (CH₂)_(r)—C₃₋₆carbocyclic residue selected from cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl; R^(5e), at each occurrence, is selected from C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(4f)R^(4f), and (CH₂)_(r)phenyl; and R^(5f), at eachoccurrence, is selected from H, methyl, ethyl, propyl, i-propyl, butyl,and cyclopropyl, cyclobutyl, and phenyl.
 9. The compound of claim 8,wherein: R⁵ is selected from methyl, ethyl, propyl, i-propyl, butyl,i-butyl, s-butyl, pentyl, hexyl, CF₃, CF₂CF₃, CF₂H, OCF₃, Cl, Br, I, F,SCF₃, NR^(5a)R^(5a), NHC(O)OR^(5a), NHC(O)R^(5b), and NHC(O)NHR^(5a);and R¹² is selected from H and methyl.
 10. A compound of claim 9,wherein: Z is —C(O)—; X is —CHR¹⁶NR¹⁷—; R¹ is selected from phenylsubstituted with 0-3 R⁴, and a 5-10 membered heteroaryl systemsubstituted with 0-2 R⁴, wherein the heteroaryl is selected fromindolyl, and pyridyl; R² is phenyl substituted with 0-2 R⁵; R³ isselected from (CRR)_(q)OH, (CRR)_(q)OR^(3d), (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)NR^(3a)R^(3a), (CHR)_(r)C(O)NR^(3a)OR^(3d),(CH₂)C(O)R^(3b), (CH₂)_(r)C(O)OR^(3d), and (CH₂)-phenyl; alternatively,R³ and R¹² join to form cyclopropyl, cyclopentyl or cyclohexyl; R^(3a)is selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl,s-butyl, t-butyl, allyl, CH₂CF₃, C(CH₃)CH₂CH₂OH, cyclopropyl,1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, andbenzyl; R^(3b) is selected from pyrrolidinyl, pyrrolid-3-enyl, andmorpholinyl; R^(3d) is selected from methyl, ethyl, propyl, i-propyl,butyl, i-butyl, t-butyl and benzyl; R is selected from H, methyl, ethyl,propyl, i-propyl, butyl, i-butyl, s-butyl, pentyl, neopentyl, phenyl andbenzyl; R⁴ is selected from methyl, ethyl, propyl, i-propyl, butyl,ethylene, OCH₃, OCF₃, SCH₃, SO₂CH₃, Cl, F, Br, CN; alternatively, two R⁴join to form —O—(CH₂)—O—; R⁶ is selected from H, methyl, ethyl, propyl,i-propyl, butyl, C(O)OCH₃, C(O)NHCH₂CH₃; R⁷, R⁹, and R¹¹ are H; R⁸ is H;R¹⁰ is selected from H and methyl; R¹⁶ is selected from H and methyl;R¹⁷ is selected from H and methyl; m is 0 or 1; l is 0 or 1 r is 0 or 1;and q is
 1. 11. The compound of claim 1, wherein R³ is H; and R⁶, isselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CRR)_(q)OH,(CRR)_(q)SH, (CRR)_(q)OR^(6d), (CRR)_(q)S(O)_(p)R^(6d),(CRR)_(r)C(O)R^(6b), (CRR)_(r)NR^(6a)R^(6a), (CRR)_(r)C(O)NR^(6a)R^(6a),(CRR)_(r)C(O)NR^(6a)OR^(6d), (CRR)SO₂NR^(6a)R^(6a),(CRR)_(r)C(O)OR^(6d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue substitutedwith 0-5 R^(6e), and a (CRR)_(r)-5-10 membered heterocyclic systemcontaining 1-4 heteroatoms selected from N, O, and S, substituted with0-3 R^(6e).
 12. The compound of claim 11, wherein R¹⁴ and R^(14a) are H;R¹⁵ is H; n is 1; R¹⁶ is selected from H, C₁₋₄ alkyl substituted with0-1 R^(16a), wherein the alkyl is selected from methyl, ethyl, propyl,i-propyl, butyl, i-butyl, and s-butyl, and C₃₋₄ cycloalkyl substitutedwith 0-3 R¹⁶a wherein the cycloalkyl is selected from cyclopropyl andcyclobutyl; R^(16a) is selected from methyl, ethyl, propyl, i-propyl,—OH, —SH, NR^(16c)R^(16c), —C(O)NR^(16c)R^(16c), and —NHC(O)R^(16c); R¹⁷is selected from H, methyl, ethyl, propyl, and i-propyl; R⁹ and R¹¹ areH; and R⁸ and R¹⁰ are independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue wherein thecarbocyclic residue is selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, phenyl and naphthyl.
 13. The compound of claim12, wherein X is CHR¹⁶R¹⁷; R⁵ is selected from methyl, ethyl, propyl,i-propyl, butyl, i-butyl, s-butyl, pentyl, hexyl, CF₃, CF₂CF₃, CF₂H,OCF₃, Cl, Br, I, F, SCF₃, NR^(5a)R^(5a), NHC(O)OR^(5a), NHC(O)R^(5b),and NHC(O)NHR^(5a); and R¹² is selected from H and methyl; Z is —C(O)—;R¹ is selected from phenyl substituted with 0-3 R⁴, and a 5-10 memberedheteroaryl system substituted with 0-2 R⁴, wherein the heteroaryl isselected from indolyl, and pyridyl; R² is phenyl substituted with 0-2R⁵; R³ is selected from (CRR)_(q)OH, (CRR)_(q)OR^(3d), (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)NR^(3a)R^(3a), (CHR)_(r)C(O)NR^(3a)OR^(3d),(CH₂)C(O)R^(3b), (CH₂)_(r)C(O)OR^(3d), and (CH₂)-phenyl; alternatively,R³ and R¹² join to form cyclopropyl, cyclopentyl or cyclohexyl; R^(3a)is selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl,s-butyl, t-butyl, allyl, CH₂CF₃, C(CH₃)CH₂CH₂OH, cyclopropyl,1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, andbenzyl; R^(3b) is selected from pyrrolidinyl, pyrrolid-3-enyl, andmorpholinyl; R^(3d) is selected from methyl, ethyl, propyl, i-propyl,butyl, i-butyl, t-butyl and benzyl; R is selected from H, methyl, ethyl,propyl, i-propyl, butyl, i-butyl, s-butyl, pentyl, neopentyl, phenyl andbenzyl; R⁴ is selected from methyl, ethyl, propyl, i-propyl, butyl,ethylene, OCH₃, OCF₃, SCH₃, SO₂CH₃, Cl, F, Br, CN; alternatively, two R⁴join to form —O—(CH₂)—O—; R⁶ is selected from H, methyl, ethyl, propyl,i-propyl, butyl, C(O)OCH₃, C(O)NHCH₂CH₃; R⁷, R⁹, and R¹¹ are H; R⁸ is H;R¹⁰ is selected from H and methyl; R¹⁶ is selected from H and methyl;R¹⁷ is selected from H and methyl; m is 0 or 1; l is 0 or 1 r is 0 or 1;and q is
 1. 14. The compound of claim 1, wherein the compound isselected from Methyl(2S)-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate;Methyl(2R)-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate;(2S)-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoicacid;(2S)-N-Methyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2R)-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-Ethyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-Benzyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-Isopropyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-Cyclopropyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-Cyclobutyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-Phenyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N,N-Dimethyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-Methyl,N-methoxy-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;Methyl(2S)-3-[[(4-chlorophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate;(2S)-3-[[(4-chlorophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-Ethyl-3-[[(4-chlorophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;Methyl(2S)-3-[[(1S/R)-1-(4-chlorophenyl)ethyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate;Methyl(2S)-3-[[(1S/R)-1-(2,4-dimethylphenyl)ethyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate;Methyl(2S)-3-[(1H-indol-3-ylmethyl)amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate;(2S)-3-[(1H-indol-3-ylmethyl)amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;Methyl(2S)-3-[(1,3-benzodioxol-5-ylmethyl)amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate;Methyl(2S)-3-[[(4-bromophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate;Methyl(2S)-2-[[[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanoate;Methyl(2S)-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanoate;(2S)-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;N-[2-[[(1S)-2-[[(2,4-dimethylphenyl)methyl]amino]-1-(hydroxymethyl)ethyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1R)-2-[[(2,4-dimethylphenyl)methyl]amino]-1-(hydroxymethyl)ethyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S/R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxypropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;tert-Butyl(3R)-4-[[(2,4-dimethylphenyl)methyl]amino]-3-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanoate;N-[2-[[(1R)-2-[[(2,4-dimethylphenyl)methyl]amino]-1-(phenylmethyl)ethyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;(2S)-N-tert-Butyl-2-[[[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-5(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(4-bromo,2-methylphenyl)methyl]amino]-2-[[[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(4-bromo,2-methylphenyl)methyl]amino]-propanamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-3-(methyl)butyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-3-(methyl)butyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(phenyl)ethyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(phenyl)ethyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-3-(phenyl)propyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-3-(phenyl)propyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-4-(methyl)pentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[([(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-4-(methyl)pentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)butyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)butyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)butyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)butyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-4-(methyl)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-4-(methyl)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-4-(methyl)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-4-(methyl)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-4,4-dimethyl-2-(hydroxy)pentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-4,4-dimethyl-2-(hydroxy)pentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-3-amino-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-3-amino-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(ethylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(ethylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(isopropylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(isopropylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[(1-pyrrolidinylcarbonyl)amino]-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[(1azetidinylcarbonyl)amino]-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[((2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(methylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-([(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(4-mopholinylcarbonyl)]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2R)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(1-piperazinylcarbonyl)]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(4-ethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(4-ethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(4-ethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(isopropylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(4-ethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[(4morpholinylcarbonyl)amino]-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(4-dimethylamino-2-methylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(4-dimethylamino-2-methylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-(tert-butyl)amino-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-isopropylamino-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-benzylamino-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-(methoxy)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2(methoxy)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;N-[2-[[(S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(methyl)propyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(methyl)propyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;N-[2-[[(S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(ethyl)butyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(ethyl)butyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;N-[2-[[(S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(propyl)pentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(S)-1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]-2-hydroxy-2-(propyl)pentyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;N-[2-[[(S)-2-[[(2,4-dimethylphenyl)methyl]amino]-1-(hydroxycyclopentyl)ethyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(S)-1-[[(S)-2-[[(2,4-dimethylphenyl)methyl]amino]-1-(hydroxycyclopentyl)ethyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethoxy)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(difluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethylthio)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(pentafluoroethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[2-amino-5-(trifluoromethoxy)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[2-amino-5-(methyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-ethylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-propylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-isobutylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[2-butylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[2-cyclohexylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-isopropylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-(tert-butyl)amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-(methylaminocarbonyl)amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-(isopropoxycarbonyl)amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-(isopropylaminocarbonyl)amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[2-(cyclohexylcarbonyl)amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[2-benzylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[2-(para-chloro)benzylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[2-[(beta-napthyl)methyl]amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[2-(meta-methyl)benzylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[2-(para-methyl)benzylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[2-(ortho-methyl)benzylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-(para-trifluoromethyl)benzylamino-5(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[3-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[3-benzylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[3-methylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[3-ethylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[3-isobutylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[3-propylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl-]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[3-butylamino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[3-(trifluoromethylcarbonyl)amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;(2S)-N-tert-Butyl-2-[[[[3-(ethoxycarbonyl)amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2,4-dimethylphenyl)methyl]amino]-propanamide;(2S)-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(2-methyl-4-bromophenyl)methyl]amino]-propanamide;(2S)-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-3-[[(4-bromophenyl)methyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(4-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(4-bromophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(4-bromo-2-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(4-methoxyphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(4-methoxy-2-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(2-methoxypyridin-5-yl)methyl]amino]-2-[[[[3(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(2,3-dimethyl-4-methoxy-phenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(4-cyano-2-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(4-ethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(2-methyl-4-vinylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(4-ethyl-2-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(4-isopropylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(4-butylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(4-dimethylaminophenyl)methyl]amino]-2-[[[[3(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(4-dimethylamino-2-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(4-methylthiophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(4-methylsulfonylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(4-trifluoromethoxyphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(3-amino-4-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(indol-3-yl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(2-methylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-3-[[(2-ethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2R)-N-Ethyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2R)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2R)-N-[(2-methyl)hydroxyprop-2-yl]-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Amyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-[(2-methyl)hydroxyprop-2-yl]-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-[(1-methyl)cycloprop-1-yl]-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-Cyclopentyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-Cyclohexyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-(β,β,β-Trifluoro)ethyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-Allyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-Cyclopropylmethyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;N-[2-[[(2S)-3-[[(2,4-dimethylphenyl)methyl]amino]-1-(pyrrolid-3-enyl)-1-oxopropyl-2-amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(2S)-3-[[(2,4-dimethylphenyl)methyl]amino]-1-(pyrrolidinyl)-1-oxopropyl-2-amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(2S)-3-[[(2,4-dimethylphenyl)methyl]amino]-1-(morpholinyl)-1-oxopropyl-2-amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;(2S)-N-Isobutyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-sec-Butyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;(2S)-N-tert-Butyl-4-[[(2,4-dimethylphenyl)methyl]amino]-3-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide;(2S,3R)-N-Ethyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide;(2S,3R)-N-Ethyl-3-[[(4-bromophenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide;Methyl(2R)-2-[[(2,4-dimethylphenyl)methyl]amino]-3-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanoate;(2R)-N-Ethyl-2-[[(2,4-dimethylphenyl)methyl]amino]-3-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;Methyl(2S)-4-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanoate;(2S)-4-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide;(2S)-N-Ethyl-4-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide;(2S)-N-Ethyl-4-[[(2,4-dimethylphenyl)methyl]methylamino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide;(2S)-N-tert-Butyl-2-[[[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzoyl]amino]acetyl]amino)-4-[[(2,4-dimethylphenyl)methyl]amino]-butanamide;(2S)-N-tert-Butyl-2-[[[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-4-[[(2,4-dimethylphenyl)methyl]methylamino]-butanamide;(2S)-N-tert-Butyl-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-4-[[(2,4-dimethylphenyl)methyl]amino]-butanamide;(2S)-N-tert-Butyl-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-4-[[(2,4-dimethylphenyl)methyl]methylamino]-butanamide;(2S)-N-tert-Butyl-2-[[[β-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-4-[[(2,4-dimethylphenyl)methyl]amino]-butanamide;(2S)-N-tert-Butyl-2-[[[[3-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-4-[[(4-ethylphenyl)methyl]amino]-butanamide;(2S)-N-tert-Butyl-4-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide;(2S)-N-tert-Butyl-4-[[(4-ethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-butanamide;(2S)-N-Ethyl-5-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-pentanamide;N-[2-[[(1S,2S/R)-1-[[[(2,4-dimethylphenyl)methyl]methylamino]methyl]-2-hydroxy-3-(methyl)butyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]methylamino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(isopropylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(2,4-dimethylphenyl)methyl]isopropylamino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(isopropylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(4-ethylphenyl)methyl]methylamino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(isopropylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[(1S,2S)-1-[[[(4-ethylphenyl)methyl]isopropylamino]methyl]-2-(hydroxy)pentyl]amino]-2-oxoethyl]-2-[[(isopropylamino)carbonyl]amino]-5-(trifluoromethyl)benzamide;(2S)-N-tert-Butyl-3-[[(2,4-dimethylphenyl)methyl]methylamino]-2-[[[[3-(trifluoromethyl)benzoyl]amino]acetyl]amino]-propanamide;N-[2-[[1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[1-[[[(4-chlorophenyl)methyl]amino]methyl]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;N-[2-[[1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]cyclopentyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]cyclopropyl]amino]-2-oxoethyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]-5-(trifluoromethyl)benzamide;N-[2-[[1-[[[(2,4-dimethylphenyl)methyl]amino]methyl]cyclopropyl]amino]-2-oxoethyl]-2-amino-5-(trifluoromethyl)benzamide;and(2S)-N-Ethyl-3-[[(2,4-dimethylphenyl)methyl]amino]-2-[[[[2-amino-5-(trifluoromethyl)benzoyl]amino]acetyl]amino]-2-methyl-propanamide.15. A pharmaceutical composition, comprising a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundof claim
 1. 16. A method for modulation of chemokine or chemokinereceptor activity comprising administering to a patient in need thereofa therapeutically effective amount of a compound of claim
 1. 17. Amethod for modulation of MCP-1, MCP-2, MCP-3 and MCP-4, and MCP-5activity that is mediated by the CCR2 receptor comprising administeringto a patient in need thereof a therapeutically effective amount of acompound of claim
 1. 18. A method for modulation of MCP-1 activitycomprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound of claim
 1. 19. A method for treating orpreventing disorders, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of claims 1,said disorders being selected from osteoarthritis, aneurism, fever,cardiovascular effects, Crohn's disease, congestive heart failure,autoimmune diseases, HIV-infection, HIV-associated dementia, psoriasis,idiopathic pulmonary fibrosis, transplant arteriosclerosis, physically-or chemically-induced brain trauma, inflammatory bowel disease,alveolitis, colitis, systemic lupus erythematosus, nephrotoxic serumnephritis, glomerularnephritis, asthma, multiple sclerosis,artherosclerosis, and rheumatoid arthritis.
 20. The method for treatingor preventing disorders, of claim 19, wherein said disorders beingselected from psoriasis, idiopathic pulmonary fibrosis, transplantarteriosclerosis, physically- or chemically-induced brain trauma,inflammatory bowel disease, alveolitis, colitis, systemic lupuserythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma,multiple sclerosis, artherosclerosis, and rheumatoid arthritis.
 21. Themethod for treating or preventing disorders, of claim 20, wherein saiddisorders being selected from alveolitis, colitis, systemic lupuserythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma,multiple sclerosis, artherosclerosis, and rheumatoid arthritis.
 22. Themethod for treating or preventing disorders, of claim 21, wherein saiddisorders being selected from asthma, multiple sclerosis,artherosclerosis, and rheumatoid arthritis.
 23. A method for treating orpreventing rheumatoid arthritis, comprising administering to a patientin need thereof a therapeutically effective amount of a compound ofclaim
 1. 24. A method for treating or preventing multiple sclerosis,comprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound of claim
 1. 25. A method for treating orpreventing atherosclerosis, comprising administering to a patient inneed thereof a therapeutically effective amount of a compound ofclaim
 1. 26. A method for treating or preventing asthma, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of claim
 1. 27. A method for treating or preventinginflammatory diseases, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of claim
 1. 28.A method for modulation of CCR2 activity comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof claim 1.